高血脂腫瘤微環境(tumor microenvironment)會藉由引發發炎反應，促進癌症發展與惡化。細胞程序死亡-配體1 (PD-L1)為一種在癌細胞膜上大量表現的檢查點蛋白(checkpoint protein)，藉由與免疫細胞膜上的PD-1受體結合，將會促進癌細胞躲避免疫細胞的抗癌反應，此機制對免疫調控與癌細胞生存相當重要，且顯著影響癌症病患預後結果。然而，高血脂腫瘤微環境與PD-L1的關係性尚未釐清，而本研究發現在自由脂肪酸(FFAs)模擬的高血脂環境下，頭頸鱗狀細胞癌(HNSCC)將會表現更強的PD-L1，且有利於HNSCC避免被巨噬細胞吞噬。此外，研究發現油酸(Oleic acid)進入細胞後會活化ERK與NF-κB這兩條促癌惡化訊息傳遞途徑，以增強PD-L1的表現。本研究不僅探討高血脂誘導表現的PD-L1在免疫抑制(immunosuppression)的角色外，也發現PD-L1可能為癌症發展中的一員，包括提高失巢凋亡抗性(anoikis resistance)、調控E-cadherin與N-cadherin等轉移相關之基因表現以及提高細胞轉移能力(metastasis)。整體來說，本研究提供高血脂腫瘤微環境可能引發更高表現程度PD-L1的證據，並且瞭解PD-L1在高血脂促進之癌症轉移的角色。

Hyperlipidemia tumor microenvironment promotes inflammation and further accelerates cancer development. Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers. While PD-L1 contact with its receptor, PD-1, on immune cells, the PD-L1/PD-1 signal will inhibit anti-tumor immune activity and triggers apoptosis of immune cells. Recently, PD-L1 in tumor have been indicated to participate in cancer development, such as metastasis and proliferation. The immune surveillance and pro-progression property play important roles in tumor evasion and significantly effects clinical outcomes. However, the relationship between hyperlipidemia and PD-L1 remains unclear. In this study, we observed that HNSCC cell lines expressed higher PD-L1 level in free fatty acids-established hyperlipidemia environment. In addition, the up-expressed PD-L1 performed tumor protection feature during macrophage-derived phagocytosis system. Furthermore, we found that oleic acid induced PD-L1 expression through the two critical signal transduction, ERK and NF-κB pathway. Interestingly, we also proposed the probability of hyperlipidemia-induced PD-L1 may participate in cancer development, such as regulating metastasis-associated genes expression, promoting metastasis ability and increasing anoikis resistance. Together, we provide the evidence that HNSCC tumor may express higher PD-L1 which increases metastasis potential in patients with hyperlipidemia.

參考文獻
Abril-Rodriguez, G. and Ribas, A. SnapShot: Immune Checkpoint Inhibitors. Cancer Cell 31, 848, 2017.

Alfieri, S., Cavalieri, S. and Licitra, L. Immunotherapy for recurrent/metastatic head and neck cancer. Current Opinion in Otolaryngology and Head and Neck Surgery 26, 152-156, 2018.

Alhamarneh, O., Amarnath, S. M., Stafford, N. D. and Greenman, J. Regulatory T cells: what role do they play in antitumor immunity in patients with head and neck cancer? Head and Neck 30, 251-261, 2008.

Alsaab, H. O., Sau, S., Alzhrani, R., Tatiparti, K., Bhise, K., Kashaw, S. K. and Iyer, A. K. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Frontiers in Pharmacology 8, 561, 2017.

Ansell, S. M., Lesokhin, A. M., Borrello, I., Halwani, A., Scott, E. C., Gutierrez, M., Schuster, S. J., Millenson, M. M., Cattry, D., Freeman, G. J., Rodig, S. J., Chapuy, B., Ligon, A. H., Zhu, L., Grosso, J. F., Kim, S. Y., Timmerman, J. M., Shipp, M. A. and Armand, P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New England Journal of Medicine 372, 311-319, 2015.

Armand, P., Nagler, A., Weller, E. A., Devine, S. M., Avigan, D. E., Chen, Y. B., Kaminski, M. S., Holland, H. K., Winter, J. N., Mason, J. R., Fay, J. W., Rizzieri, D. A., Hosing, C. M., Ball, E. D., Uberti, J. P., Lazarus, H. M., Mapara, M. Y., Gregory, S. A., Timmerman, J. M., Andorsky, D., Or, R., Waller, E. K., Rotem-Yehudar, R. and Gordon, L. I. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. Journal of Clinical Oncology 31, 4199-4206, 2013.

Azuma, K., Ota, K., Kawahara, A., Hattori, S., Iwama, E., Harada, T., Matsumoto, K., Takayama, K., Takamori, S., Kage, M., Hoshino, T., Nakanishi, Y. and Okamoto, I. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Annals of Oncology 25, 1935-1940, 2014.

Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J. and Ahmed, R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687, 2006.

Bauernhofer, T., Kuss, I., Henderson, B., Baum, A. S. and Whiteside, T. L. Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. European Journal of Immunology 33, 119-124, 2003.

Bays, H. E., Toth, P. P., Kris-Etherton, P. M., Abate, N., Aronne, L. J., Brown, W. V., Gonzalez-Campoy, J. M., Jones, S. R., Kumar, R., La Forge, R. and Samuel, V. T. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. Journal of Clinical Lipidology 7, 304-383, 2013.

Beck, K. E., Blansfield, J. A., Tran, K. Q., Feldman, A. L., Hughes, M. S., Royal, R. E., Kammula, U. S., Topalian, S. L., Sherry, R. M., Kleiner, D., Quezado, M., Lowy, I., Yellin, M., Rosenberg, S. A. and Yang, J. C. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. Journal of Clinical Oncology 24, 2283-2289, 2006.

Becker, J. C., Andersen, M. H., Schrama, D. and Thor Straten, P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunology, Immunotherapy 62, 1137-1148, 2013.

Bhave, S. L., Teknos, T. N. and Pan, Q. Molecular parameters of head and neck cancer metastasis. Critical Reviews in Eukaryotic Gene Expression 21, 143-153, 2011.

Bhowmick, N. A., Chytil, A., Plieth, D., Gorska, A. E., Dumont, N., Shappell, S., Washington, M. K., Neilson, E. G. and Moses, H. L. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848-851, 2004.

Björntorp, P., Bergman, H. and Varnauskas, E. Plasma free fatty acid turnover rate in obesity. Acta Medica Scandinavica 185, 351-356, 1969.

Blank, C. U. and Enk, A. Therapeutic use of anti-CTLA-4 antibodies. International Immunology 27, 3-10, 2015.

Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., Xiang, X., Luo, Z. and Ruderman, N. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 54, 3458-3465, 2005.

Boden, G. Obesity, insulin resistance and free fatty acids. Current Opinion in Endocrinology, Diabetes and Obesity 18, 139-143, 2011.

Bonner, J. A., Harari, P. M., Giralt, J., Azarnia, N., Shin, D. M., Cohen, R. B., Jones, C. U., Sur, R., Raben, D., Jassem, J., Ove, R., Kies, M. S., Baselga, J., Youssoufian, H., Amellal, N., Rowinsky, E. K. and Ang, K. K. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England Journal of Medicine 354, 567-578, 2006.

Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., Chow, L. Q., Vokes, E. E., Felip, E., Holgado, E., Barlesi, F., Kohlhäufl, M., Arrieta, O., Burgio, M. A., Fayette, J., Lena, H., Poddubskaya, E., Gerber, D. E., Gettinger, S. N., Rudin, C. M., Rizvi, N., Crinò, L., Blumenschein, G. R. Jr., Antonia, S. J., Dorange, C., Harbison, C. T., Graf Finckenstein, F. and Brahmer, J. R. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. The New England Journal of Medicine 373, 1627-1639, 2015.

Brahmer, J. R., Tykodi, S. S., Chow, L. Q., Hwu, W. J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., Pitot, H. C., Hamid, O., Bhatia, S., Martins, R., Eaton, K., Chen, S., Salay, T. M., Alaparthy, S., Grosso, J. F., Korman, A. J., Parker, S. M., Agrawal, S., Goldberg, S. M., Pardoll, D. M., Gupta, A. and Wigginton, J. M. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The New England Journal of Medicine 366, 2455-2465, 2012.

Brunet, J. F., Denizot, F., Luciani, M. F., Roux-Dosseto, M., Suzan, M., Mattei, M. G. and Golstein, P. A new member of the immunoglobulin superfamily--CTLA-4. Nature 328, 267-270, 1987.

Bryce, D. P., Ireland, P. E. and Rider, W. D. Experience in the surgical and radiological treatment in 500 cases of carcinoma of the larynx. Annals of Otology, Rhinology, and Laryngology 72, 416-430, 1963.

Bryce, D. P. and Rider, W. D. Pre-operative irradiation in the treatment of advanced laryngeal carcinoma. The Laryngoscope 81, 1481-1490, 1971.

Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H. and Freeman, G. J. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111-122, 2007.

Chambers, C. A., Kuhns, M. S. and Allison, J. P. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proceedings of the National Academy of Sciences of the United States of America 96, 8603-8608, 1999.

Champiat, S., Dercle, L., Ammari, S., Massard, C., Hollebecque, A., Postel-Vinay, S., Chaput, N., Eggermont, A., Marabelle, A., Soria, J. C. and Ferté, C. Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1. Clinical Cancer Research 23, 1920-1928, 2017.

Chan, S. H., Tsai, J. P., Shen, C. J., Liao, Y. H. and Chen, B. K. Oleate-induced PTX3 promotes head and neck squamous cell carcinoma metastasis through the up-regulation of vimentin. Oncotarget 8, 41364-41378, 2017.

Chang, H. C., Yang, H. C., Chang, H. Y., Yeh, C. J., Chen, H. H., Huang, K. C. and Pan, W. H. Morbid obesity in Taiwan: Prevalence, trends, associated social demographics, and lifestyle factors. Public Library of Science One 12, e0169577, 2017.

Chen, H., Li, C., Peng, X., Zhou, Z., Weinstein, J. N., Cancer Genome Atlas Research Network and Liang, H. A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples. Cell 173, 386-399, 2018.

Cho, Y. A., Yoon, H. J., Lee, J. I., Hong, S. P. and Hong, S. D. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncology 47, 1148-1153, 2011.

Chow, L. Q. M., Haddad, R., Gupta, S., Mahipal, A., Mehra, R., Tahara, M., Berger, R., Eder, J. P., Burtness, B., Lee, S. H., Keam, B., Kang, H., Muro, K., Weiss, J., Geva, R., Lin, C. C., Chung, H. C., Meister, A., Dolled-Filhart, M., Pathiraja, K., Cheng, J. D. and Seiwert, T. Y. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. Journal of Clinical Oncology 34, 3838-3845, 2016.

Concha-Benavente, F., Srivastava, R., Ferrone, S. and Ferris, R. L. Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells. Oral Oncology 58, 52-58, 2016a.

Concha-Benavente, F., Srivastava, R., Trivedi, S., Lei, Y., Chandran, U., Seethala, R. R., Freeman, G. J. and Ferris, R. L. Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer. Cancer Research 76, 1031-1043, 2016b.

da Silva, S. D., Cunha, I. W., Nishimoto, I. N., Soares, F. A., Carraro, D. M., Kowalski, L. P. and Graner, E. Clinicopathological significance of ubiquitin-specific protease 2a (USP2a), fatty acid synthase (FASN), and ErbB2 expression in oral squamous cell carcinomas. Oral Oncology 45, e134-139, 2009.

Daigneault, M., Preston, J. A., Marriott, H. M., Whyte, M. K. and Dockrell, D. H. The identification of markers of macrophage differentiation in PMA-stimulated THP-1 cells and monocyte-derived macrophages. Public Library of Science One 5, e8668, 2010.

Dasgupta, S., Bhattacharya-Chatterjee, M., O'Malley, B. W. Jr. and Chatterjee, S. K. Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. Journal of Immunology 175, 5541-5550, 2005.

Day, S. D., Enos, R. T., McClellan, J. L., Steiner, J. L., Velázquez, K. T. and Murphy, E. A. Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer. Cytokine 64, 454-462, 2013.

de Visser, K. E., Eichten, A. and Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nature Reviews Cancer 6, 24-37, 2006.

Debatin, K. M. The role of CD95 system in chemotherapy. Drug Resistance Updates 2, 85-90, 1999.

Decker, J. and Goldstein, J. C. Risk factors in head and neck cancer. The New England Journal of Medicine 306, 1151-1155, 1982.

Dong, H., Zhu, G., Tamada, K. and Chen, L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine 5, 1365-1369, 1999.

Du, S., McCall, N., Park, K., Guan, Q., Fontina, P., Ertel, A., Zhan, T., Dicker, A. P. and Lu, B. Blockade of Tumor-Expressed PD-1 promotes lung cancer growth. OncoImmunology 7, e1408747, 2018.

Ferris, R. L. Immunology and Immunotherapy of Head and Neck Cancer. Journal of Clinical Oncology 33, 3293-3304, 2015.

Ferris, R. L., Blumenschein, G. Jr., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Iglesias Docampo, L. C., Haddad, R., Rordorf, T., Kiyota, N., Tahara, M., Monga, M., Lynch, M., Geese, W. J., Kopit, J., Shaw, J. W. and Gillison, M. L. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. The New England Journal of Medicine 375, 1856-1867, 2016.

Fife, B. T., Pauken, K. E., Eagar, T. N., Obu, T., Wu, J., Tang, Q., Azuma, M., Krummel, M. F. and Bluestone, J. A. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nature Immunology 10, 1185-1192, 2009.

Flegal, K. M. Epidemiologic aspects of overweight and obesity in the United States. Physiology and Behavior 86, 599-602, 2005.

Flegal, K. M., Kruszon-Moran, D., Carroll, M. D., Fryar, C. D. and Ogden, C. L. Trends in Obesity Among Adults in the United States, 2005 to 2014. Journal of the American Medical Association 315, 2284-2291, 2016.
Forster, M. D. and Devlin, M. J. Immune Checkpoint Inhibition in Head and Neck Cancer. Frontiers in Oncology 8, 310, 2018.

Freeman, G. J., Long, A. J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L. J., Malenkovich, N., Okazaki, T., Byrne, M. C., Horton, H. F., Fouser, L., Carter, L., Ling, V., Bowman, M. R., Carreno, B. M., Collins, M., Wood, C R. and Honjo, T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. The Journal of Experimental Medicine 192, 1027-1034, 2000.

Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., Tosolini, M., Camus, M., Berger, A., Wind, P., Zinzindohoué, F., Bruneval, P., Cugnenc, P. H., Trajanoski, Z., Fridman, W. H. and Pagès, F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960-1964, 2006.

Gao, Q., Wang, X. Y., Qiu, S. J., Yamato, I., Sho, M., Nakajima, Y., Zhou, J., Li, B. Z., Shi, Y. H., Xiao, Y. S., Xu, Y. and Fan, J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clinical Cancer Research 15, 971-979, 2009.

Garcia-Diaz, A., Shin, D. S., Moreno, B. H., Saco, J., Escuin-Ordinas, H., Rodriguez, G. A., Zaretsky, J. M., Sun, L., Hugo, W., Wang, X., Parisi, G., Saus, C. P., Torrejon, D. Y., Graeber, T. G., Comin-Anduix, B., Hu-Lieskovan, S., Damoiseaux, R., Lo, R. S. and Ribas, A. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Reports 19, 1189-1201, 2017.
Gildener-Leapman, N., Ferris, R. L. and Bauman, J. E. Promising systemic immunotherapies in head and neck squamous cell carcinoma. Oral Oncology 49, 1089-1096, 2013.

Giovannucci, E. Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. The American Journal of Clinical Nutrition 86, 836S-842S, 2007.

Gordon, S. R., Maute, R. L., Dulken, B. W., Hutter, G., George, B. M., McCracken, M. N., Gupta, R., Tsai, J. M., Sinha, R., Corey, D., Ring, A. M., Connolly, A. J. and Weissman, I. L. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495-499, 2017.

Grundy, S. M. Obesity, metabolic syndrome, and cardiovascular disease. Journal of Clinical Endocrinology and Metabolism 89, 2595-2600, 2004.

Hamid, O., Robert, C., Daud, A., Hodi, F. S., Hwu, W. J., Kefford, R., Wolchok, J. D., Hersey, P., Joseph, R. W., Weber, J. S., Dronca, R., Gangadhar, T. C., Patnaik, A., Zarour, H., Joshua, A. M., Gergich, K., Elassaiss-Schaap, J., Algazi, A., Mateus, C., Boasberg, P., Tumeh, P. C., Chmielowski, B., Ebbinghaus, S. W., Li, X. N., Kang, S. P. and Ribas, A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. The New England Journal of Medicine 369, 134-144, 2013.

Hanahan, D. and Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, 2011.

Hardy, S., St-Onge, G. G., Joly, E., Langelier, Y. and Prentki, M. Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40. Journal of Biological Chemistry 280, 13285-13291, 2005.

Hazan, R. B., Qiao, R., Keren, R., Badano, I. and Suyama, K. Cadherin switch in tumor progression. Annals of the New York Academy of Sciences 1014, 155-163, 2004.

Hino, R., Kabashima, K., Kato, Y., Yagi, H., Nakamura, M., Honjo, T., Okazaki, T. and Tokura, Y. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116, 1757-1766, 2010.

Hodi, F. S., Mihm, M. C., Soiffer, R. J., Haluska, F. G., Butler, M., Seiden, M. V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M. T., Shankar, S., Chen, T. C., Korman, A., Allison, J. P. and Dranoff, G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proceedings of the National Academy of Sciences of the United States of America 100, 4712-4717, 2003.

Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., Akerley, W., van den Eertwegh, A. J., Lutzky, J., Lorigan, P., Vaubel, J. M., Linette, G. P., Hogg, D., Ottensmeier, C. H., Lebbé, C., Peschel, C., Quirt, I., Clark, J. I., Wolchok, J. D., Weber, J. S., Tian, J., Yellin, M. J., Nichol, G. M., Hoos, A. and Urba, W. J. Improved survival with ipilimumab in patients with metastatic melanoma. The New England Journal of Medicine 363, 711-723, 2010.

Howell, G. M. and Grandis, J. R. Molecular mediators of metastasis in head and neck squamous cell carcinoma. Head and Neck 27, 710-717, 2005.

Hu, Q., Peng, J., Chen, X., Li, H., Song, M., Cheng, B. and Wu, T. Obesity and genes related to lipid metabolism predict poor survival in oral squamous cell carcinoma. Oral Oncology 89, 14-22, 2019.

Huang, P., Han, J. and Hui, L. MAPK signaling in inflammation-associated cancer development. Protein and Cell 1, 218-226, 2010.

Huard, B., Gaulard, P., Faure, F., Hercend, T. and Triebel, F. Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand. Immunogenetics 39, 213-217, 1994.

Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M., Wallweber, H. A., Sasmal, D. K., Huang, J., Kim, J. M., Mellman, I. and Vale, R. D. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428-1433, 2017.

Ishida, Y., Agata, Y., Shibahara, K. and Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. The European Molecular Biology Organization Journal 11, 3887-3895, 1992.

Itani, S. I., Ruderman, N. B., Schmieder, F. and Boden, G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51, 2005-2011, 2002.

Iwai, Y., Ishida, M., Tanaka, Y., Okazaki, T., Honjo, T. and Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the National Academy of Sciences of the United States of America 99, 12293-12297, 2002.

Jiang, X., Wang, J., Deng, X., Xiong, F., Ge, J., Xiang, B., Wu, X., Ma, J., Zhou, M., Li, X., Li, Y., Li, G., Xiong, W., Guo, C. and Zeng, Z. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Molecular Cancer 18, 10, 2019.

Jie, H. B., Schuler, P. J., Lee, S. C., Srivastava, R. M., Argiris, A., Ferrone, S., Whiteside, T. L. and Ferris, R. L. CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis. Cancer Research 75, 2200-2210, 2015.

Kammertoens, T., Schüler, T. and Blankenstein, T. Immunotherapy: target the stroma to hit the tumor. Trends in Molecular Medicine 11, 225-231, 2005.

Kamphorst, A. O., Wieland, A., Nasti, T., Yang, S., Zhang, R., Barber, D. L., Konieczny, B. T., Daugherty, C. Z., Koenig, L., Yu, K., Sica, G. L., Sharpe, A. H., Freeman, G. J., Blazar, B. R., Turka, L. A., Owonikoko, T. K., Pillai, R. N., Ramalingam, S. S., Araki, K. and Ahmed, R. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355, 1423-1427, 2017.

Karin, M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harbor Perspectives in Biology 1, a000141, 2009.

Kato, S., Goodman, A., Walavalkar, V., Barkauskas, D. A., Sharabi, A. and Kurzrock R. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clinical Cancer Research 23, 4242-4250, 2017.

Kitamura, T., Qian, B. Z. and Pollard, J. W. Immune cell promotion of metastasis. Nature Reviews Immunology 15, 73-86, 2015.

Kleffel, S., Posch, C., Barthel, S. R., Mueller, H., Schlapbach, C., Guenova, E., Elco, C. P., Lee, N., Juneja, V. R., Zhan, Q., Lian, C. G., Thomi, R., Hoetzenecker, W., Cozzio, A., Dummer, R., Mihm, M. C. Jr., Flaherty, K. T., Frank, M. H., Murphy, G. F., Sharpe, A. H., Kupper, T. S. and Schatton, T. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell 162, 1242-1256, 2015.

Ko, H., Kim, S., Jin, C. H., Lee, E., Ham, S., Yook, J. I. and Kim, K. Protein kinase casein kinase 2-mediated upregulation of N-cadherin confers anoikis resistance on esophageal carcinoma cells. Molecular Cancer Research 10, 1032-1038, 2012.

Konishi, J., Yamazaki, K., Azuma, M., Kinoshita, I., Dosaka-Akita, H. and Nishimura, M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clinical Cancer Research 10, 5094-5100, 2004.

Kruyt, F. A. and Schuringa, J. J. Apoptosis and cancer stem cells: Implications for apoptosis targeted therapy. Biochemical Pharmacology 80, 423-430, 2010.
Kryczek, I., Wu, K., Zhao, E., Wei, S., Vatan, L., Szeliga, W., Huang, E., Greenson, J., Chang, A., Roliński, J., Radwan, P., Fang, J., Wang, G. and Zou, W. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. Journal of Immunology 186, 4388-4395, 2011.

Kuss, I., Hathaway, B., Ferris, R. L., Gooding, W. and Whiteside, T. L. Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clinical Cancer Research 10, 3755-3762, 2004.

Lee, H. H., Wang, Y. N., Xia, W., Chen, C. H., Rau, K. M., Ye, L., Wei, Y., Chou, C. K., Wang, S. C., Yan, M., Tu, C. Y., Hsia, T. C., Chiang, S. F., Chao, K. S. C., Wistuba, I. I., Hsu, J. L., Hortobagyi, G. N. and Hung, M. C. Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy. Cancer Cell 36, 168-178, 2019.

Legrand, N., Huntington, N. D., Nagasawa, M., Bakker, A. Q., Schotte, R., Strick-Marchand, H., de Geus, S. J., Pouw, S. M., Böhne, M., Voordouw, A., Weijer, K., Di Santo, J. P. and Spits, H. Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proceedings of the National Academy of Sciences of the United States of America 108, 13224-13229, 2011.

Leibowitz, M. S., Andrade Filho, P. A., Ferrone, S. and Ferris, R. L. Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer Immunology, Immunotherapy 60, 525-535, 2011.

Li, C. W., Lim, S. O., Xia, W., Lee, H. H., Chan, L. C., Kuo, C. W., Khoo, K. H., Chang, S. S., Cha, J. H., Kim, T., Hsu, J. L., Wu, Y., Hsu, J. M., Yamaguchi, H., Ding, Q., Wang, Y., Yao, J., Lee, C. C., Wu, H. J., Sahin, A. A., Allison, J. P., Yu, D., Hortobagyi G. N. and Hung M. C. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nature Communications 7, 12632, 2016.

Li, J., Chen, L., Xiong, Y., Zheng, X., Xie, Q., Zhou, Q., Shi, L., Wu, C., Jiang, J. and Wang, H. Knockdown of PD-L1 in Human Gastric Cancer Cells Inhibits Tumor Progression and Improves the Cytotoxic Sensitivity to CIK Therapy. Cellular Physiology and Biochemistry 41, 907-920, 2017.

Liao, C. T., Wang, H. M., Chang, J. T., Ng, S. H., Hsueh, C., Lee, L. Y., Lin, C. H., Chen, I. H., Huang, S. F. and Yen, T. C. Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity. Cancer 110, 1501-1508, 2007.

Liao, Y. H., Chiang, K. H., Shieh, J. M., Huang, C. R., Shen, C. J., Huang, W. C. and Chen, B. K. Epidermal growth factor-induced ANGPTL4 enhances anoikis resistance and tumour metastasis in head and neck squamous cell carcinoma. Oncogene 36, 2228-2242, 2017.

Lim, S. O., Li, C. W., Xia, W., Cha, J. H., Chan, L. C., Wu, Y., Chang, S. S., Lin, W. C., Hsu, J. M., Hsu, Y. H., Kim, T., Chang, W. C., Hsu, J. L., Yamaguchi, H., Ding, Q., Wang, Y., Yang, Y., Chen, C. H., Sahin, A. A., Yu, D., Hortobagyi, G. N. and Hung, M. C. Deubiquitination and Stabilization of PD-L1 by CSN5. Cancer Cell 30, 925-939, 2016.

Lin, S. J., Chin, Y. T., Ho, Y., Chou, S. Y., Sh Yang, Y. C., Nana, A. W., Su, K. W., Lim, Y. T., Wang, K., Lee, S. Y., Shih, Y. J., Chen, Y. R., Whang-Peng, J., Davis, P. J., Lin, H. Y. and Fu, E. Nano-diamino-tetrac (NDAT) inhibits PD-L1 expression which is essential for proliferation in oral cancer cells. Food and Chemical Toxicology 120, 1-11, 2018.

Lin, Y. M., Sung, W. W., Hsieh, M. J., Tsai, S. C., Lai, H. W., Yang, S. M., Shen, K. H., Chen, M. K., Lee, H., Yeh, K. T. and Chen, C. J. High PD-L1 Expression Correlates with Metastasis and Poor Prognosis in Oral Squamous Cell Carcinoma. Public Library of Science One 10, e0142656, 2015.

Linsley, P. S., Brady, W., Urnes, M., Grosmaire, L. S., Damle, N. K. and Ledbetter, J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. Journal of Experimental Medicine 174, 561-569, 1991.

López-Albaitero, A., Nayak, J. V., Ogino, T., Machandia, A., Gooding, W., DeLeo, A. B., Ferrone, S. and Ferris, R. L. Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. Journal of Immunology 176, 3402-3409, 2006.

Love, R. R., Leventhal, H., Easterling, D. V. and Nerenz, D. R. Side effects and emotional distress during cancer chemotherapy. Cancer 63, 604-612, 1989.

Maa, M. C., Lee, J. C., Chen, Y. J., Chen, Y. J., Lee, Y. C., Wang, S. T., Huang, C. C., Chow, N. H. and Leu, T. H. Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase. Journal of Biological Chemistry 282, 19399-19409, 2007.
Mandviwala, T., Khalid, U. and Deswal, A. Obesity and Cardiovascular Disease: a Risk Factor or a Risk Marker? Current Atherosclerosis Reports 18, 21, 2016.

Mao, L., Hong, W. K. and Papadimitrakopoulou, V. A. Focus on head and neck cancer. Cancer Cell 5, 311-316, 2004.

Mattijssen, V., Peters, H. M., Schalkwijk, L., Manni, J. J., van 't Hof-Grootenboer, B., de Mulder, P. H. and Ruiter, D. J. E-cadherin expression in head and neck squamous-cell carcinoma is associated with clinical outcome. International Journal of Cancer 55, 580-585, 1993.

Menendez, J. A. and Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Reviews Cancer 7, 763-777, 2007.

Monney, L., Sabatos, C. A., Gaglia, J. L., Ryu, A., Waldner, H., Chernova, T., Manning, S., Greenfield, E. A., Coyle, A. J., Sobel, R. A., Freeman, G. J. and Kuchroo, V. K. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536-541, 2002.

Moore, L. L., Chadid, S., Singer, M. R., Kreger, B. E. and Denis, G. V. Metabolic health reduces risk of obesity-related cancer in framingham study adults. Cancer Epidemiology, Biomarkers and Prevention 23, 2057-2065, 2014.

Müller, T., Braun, M., Dietrich, D., Aktekin, S., Höft, S., Kristiansen, G., Göke, F., Schröck, A., Brägelmann, J., Held, S. A. E., Bootz, F. and Brossart, P. PD-L1: a novel prognostic biomarker in head and neck squamous cell carcinoma. Oncotarget 8, 52889-52900, 2017.

Nishioka, N., Matsuoka T., Yashiro, M., Hirakawa, K., Olden, K. and Roberts, J. D. Linoleic acid enhances angiogenesis through suppression of angiostatin induced by plasminogen activator inhibitor 1. British Journal of Cancer 105, 1750-1758, 2011.

Nead, K. T., Sharp, S. J., Thompson, D. J., Painter, J. N., Savage, D. B., Semple, R. K., Barker, A., Australian National Endometrial Cancer Study Group (ANECS), Perry, J. R., Attia J., Dunning, A. M., Easton, D. F., Holliday, E., Lotta, L. A., O'Mara, T., McEvoy, M., Pharoah, P. D., Scott, R. J., Spurdle, A. B., Langenberg, C., Wareham, N. J. and Scott, R. A. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. Journal of the National Cancer Institute 107, djv178, 2015.

Nghiem, P. T., Bhatia, S., Lipson, E. J., Kudchadkar, R. R., Miller, N. J., Annamalai, L., Berry, S., Chartash, E. K., Daud, A., Fling, S. P., Friedlander, P. A., Kluger, H. M., Kohrt, H. E., Lundgren, L., Margolin, K., Mitchell, A., Olencki, T., Pardoll, D. M., Reddy, S. A., Shantha, E. M., Sharfman, W. H., Sharon, E., Shemanski, L. R., Shinohara, M. M., Sunshine, J. C., Taube, J. M., Thompson, J. A., Townson, S. M., Yearley, J. H., Topalian, S. L. and Cheever, M. A. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. The New England Journal of Medicine 374, 2542-2552, 2016.

Nguyen, P. T., Kudo, Y., Yoshida, M., Kamata, N., Ogawa, I. and Takata, T. N-cadherin expression is involved in malignant behavior of head and neck cancer in relation to epithelial-mesenchymal transition. Histology and Histopathology 26, 147-156, 2011.

Ni, L., Ma, C. J., Zhang, Y., Nandakumar, S., Zhang, C. L., Wu, X. Y., Borthwick, T., Hamati, A., Chen, X. Y., Kumaraguru, U., Moorman, J. P. and Yao, Z. Q. PD-1 modulates regulatory T cells and suppresses T-cell responses in HCV-associated lymphoma. Immunology and Cell Biology 89, 535-539, 2011.

Nielsen, S. F., Nordestgaard, B. G. and Bojesen, S. E. Statin use and reduced cancer-related mortality. The New England Journal of Medicine 367, 1792-1802, 2012.

O-Charoenrat, P., Rhys-Evans, P., Modjtahedi, H., Court, W., Box, G. and Eccles, S. Overexpression of epidermal growth factor receptor in human head and neck squamous carcinoma cell lines correlates with matrix metalloproteinase-9 expression and in vitro invasion. International Journal of Cancer 86, 307-317, 2000.

Parsa, A. T., Waldron, J. S., Panner, A., Crane, C. A., Parney, I. F., Barry, J. J., Cachola, K. E., Murray, J. C., Tihan, T., Jensen, M. C., Mischel, P. S., Stokoe, D. and Pieper, R. O. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nature Medicine 13, 84-88, 2007.

Patel, S. P. and Kurzrock, R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Molecular Cancer Therapeutics 14, 847-856, 2015.

Patel, V., Marsh, C. A., Dorsam, R. T., Mikelis, C. M., Masedunskas, A., Amornphimoltham, P., Nathan, C. A., Singh, B., Weigert, R., Molinolo, A. A. and Gutkind, J. S. Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Research 71, 7103-7112, 2011.

Pietrzyk, L., Torres, A., Maciejewski, R. and Torres, K. Obesity and Obese-related Chronic Low-grade Inflammation in Promotion of Colorectal Cancer Development. Asian Pacific Journal of Cancer Prevention 16, 4161-4168, 2015.

Pignon, J. P., Syz, N., Posner, M., Olivares, R., Le Lann, L., Yver, A., Dunant, A., Lewin, F., Dalley, D. N., Paccagnella, A., Taylor, S. G., Domenge, C., Bourhis, J. and Mazumdar, M. Adjusting for patient selection suggests the addition of docetaxel to 5-fluorouracil-cisplatin induction therapy may offer survival benefit in squamous cell cancer of the head and neck. Anti-Cancer Drugs 15, 331-340, 2004.

Pignon, J. P., le Maître, A., Maillard, E., Bourhis, J. and MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and Oncology 92, 4-14, 2009.

Pillai, R. N., Behera, M., Owonikoko, T. K., Kamphorst, A. O., Pakkala, S., Belani, C. P., Khuri, F. R., Ahmed, R. and Ramalingam, S. S. Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: A systematic analysis of the literature. Cancer 124, 271-277, 2018.

Ragin, C. C., Modugno, F. and Gollin, S. M. The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. Journal of Dental Research 86, 104-114, 2007.

Ralainirina, N., Poli, A., Michel, T., Poos, L., Andrès, E., Hentges, F. and Zimmer, J. Control of NK cell functions by CD4+CD25+ regulatory T cells. Journal of Leukocyte Biology 81, 144-153, 2007.

Ramsay, A. G. Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell immunity. British Journal of Haematology 162, 313-325, 2013.

Ritprajak, P. and Azuma, M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncology 51, 221-228, 2015.

Roepman, P., de Jager, A., Groot Koerkamp, M. J., Kummer, J. A., Slootweg, P. J. and Holstege, F. C. Maintenance of head and neck tumor gene expression profiles upon lymph node metastasis. Cancer Research 66, 11110-11114, 2006.

Roepman, P., Wessels, L. F., Kettelarij, N., Kemmeren, P., Miles, A. J., Lijnzaad, P., Tilanus, M. G., Koole, R., Hordijk, G. J., van der Vliet, P. C., Reinders, M. J., Slootweg, P. J. and Holstege, F. C. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nature Genetics 37, 182-186, 2005.

Rooney, M., Kish, J., Jacobs, J., Kinzie, J., Weaver, A., Crissman, J. and Al-Sarraf, M. Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 55, 1123-1128, 1985.

Rosenthal, E. L. and Matrisian, L. M. Matrix metalloproteases in head and neck cancer. Head and Neck 28, 639-648, 2006.

Saâda-Bouzid, E., Defaucheux, C., Karabajakian, A., Coloma, V. P., Servois, V., Paoletti, X., Even, C., Fayette, J., Guigay, J., Loirat, D., Peyrade, F., Alt, M., Gal, J. and Le Tourneau, C. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Annals of Oncology 28, 1605-1611, 2017.
Schwab, K. S., Kristiansen, G., Schild, H. H., Held, S. E. A., Heine, A. and Brossart, P. Successful Treatment of Refractory Squamous Cell Cancer of the Head and Neck with Nivolumab and Ipilimumab. Case Reports in Oncology 11, 17-20, 2018.

Segal, N. H., Ou, S. I., Balmanoukian, A., Massarelli, E., Brahmer, J. R., Weiss J., Schoffski, P., Antonia, S. J., Massard, C., Zandberg, D. P., Maher, C., Khleif, S. N., Jin, X., Rebelatto, M. C., Steele K. E., Antal J., Gupta, A. and Spreafico A. Updated safety and efficacy of durvalumab (MEDI4736), an anti-PD-L 1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. Annals of Oncology 27, 9490, 2016.

Sen, M., Pollock, N. I., Black, J., DeGrave, K. A., Wheeler, S., Freilino, M. L., Joyce, S., Lui, V. W., Zeng, Y., Chiosea, S. I. and Grandis, J. R. JAK kinase inhibition abrogates STAT3 activation and head and neck squamous cell carcinoma tumor growth. Neoplasia 17, 256-264, 2015.

Shen, C. J., Chan, S. H., Lee, C. T., Huang, W. C., Tsai, J. P. and Chen, B. K. Oleic acid-induced ANGPTL4 enhances head and neck squamous cell carcinoma anoikis resistance and metastasis via up-regulation of fibronectin. Cancer Letters 386, 110-122, 2017.

Shen, Y., Wang, C., Ren, Y. and Ye, J. A comprehensive look at the role of hyperlipidemia in promoting colorectal cancer liver metastasis. Journal of Cancer 9, 2981-2986, 2018.

Shi, S. J., Wang, L. J., Wang, G. D., Guo, Z. Y., Wei, M., Meng, Y. L., Yang, A. G. and Wen, W. H. B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. Public Library of Science One 8, e76012, 2013.

Shi, Y. Regulatory mechanisms of PD-L1 expression in cancer cells. Cancer Immunology, Immunotherapy 67, 1481-1489, 2018.

Siegel, R. L., Miller, K. D. and Jemal, A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians 69, 7-34, 2019.

Silva, S. D., Cunha, I. W., Younes, R. N., Soares, F. A., Kowalski, L. P. and Graner, E. ErbB receptors and fatty acid synthase expression in aggressive head and neck squamous cell carcinomas. Oral Diseases 16, 774-780, 2010.

Simpson, C. D., Anyiwe, K. and Schimmer, A. D. Anoikis resistance and tumor metastasis. Cancer Letters 272, 177-185, 2008.

Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., Walsh, L. A., Postow, M. A., Wong, P., Ho, T. S., Hollmann, T. J., Bruggeman, C., Kannan, K., Li, Y., Elipenahli, C., Liu, C., Harbison, C. T., Wang, L., Ribas, A., Wolchok, J. D. and Chan, T. A. Genetic basis for clinical response to CTLA-4 blockade in melanoma. The New England Journal of Medicine 371, 2189-2199, 2014.

Son, C. H., Bae, J. H., Shin, D. Y., Lee, H. R., Choi, Y. J., Jo, W. S., Ho Jung, M., Kang, C. D., Yang, K. and Park, Y. S. CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model. Journal of Immunotherapy 37, 1-7, 2014.

Stokes, W. A., Eguchi, M., Amini, A., Hararah, M. K., Ding, D., McDermott, J. D., Bradley, C. J. and Karam, S. D. Survival impact and toxicity of metformin in head and neck cancer: An analysis of the SEER-Medicare dataset. Oral Oncology 84, 12-19, 2018.

Straub, M., Drecoll, E., Pfarr, N., Weichert, W., Langer, R., Hapfelmeier, A., Götz, C., Wolff, K. D., Kolk, A. and Specht, K. CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity. Oncotarget 7, 12024-12034, 2016.

Strauss, L., Bergmann, C., Gooding, W., Johnson, J. T. and Whiteside, T. L. The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clinical Cancer Research 13, 6301-6311, 2007.

Sturgis, E. M. and Cinciripini, P. M. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer 110, 1429-1435, 2007.

Suh, Y., Amelio, I., Guerrero Urbano, T. and Tavassoli, M. Clinical update on cancer: molecular oncology of head and neck cancer. Cell Death and Disease 5, e1018, 2014.

Sundar, R., Cho, B. C., Brahmer, J. R. and Soo, R. A. Nivolumab in NSCLC: latest evidence and clinical potential. Therapeutic Advances in Medical Oncology 7, 85-96, 2015.

Taube, J. M., Anders, R. A., Young, G. D., Xu, H., Sharma, R., McMiller, T. L., Chen, S., Klein, A. P., Pardoll, D. M., Topalian, S. L. and Chen, L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science Translational Medicine 4, 127ra37, 2012.

Thomas, S. M., Coppelli, F. M., Wells, A., Gooding, W. E., Song, J., Kassis, J., Drenning, S. D. and Grandis, J. R. Epidermal growth factor receptor-stimulated activation of phospholipase Cgamma-1 promotes invasion of head and neck squamous cell carcinoma. Cancer Research 63, 5629-5635, 2003.

Thompson, R. H., Kuntz, S. M., Leibovich, B. C., Dong, H., Lohse, C. M., Webster, W. S., Sengupta, S., Frank, I., Parker, A. S., Zincke, H., Blute, M. L., Sebo, T. J., Cheville, J. C. and Kwon, E. D. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Research 66, 3381-3385, 2006.

Tierney, A. and Taylor, J. Chemotherapy-induced hair loss. Nursing Standard 5, 29-31, 1991.

Toohill, R. J., Anderson, T., Byhardt, R. W., Cox, J. D., Duncavage, J. A., Grossman, T. W., Haas, C. D., Haas, J. S., Hartz, A. J., Libnoch, J. A., Malin, T. C., Ritch, P. S. and Wilson, J. F. Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. A preliminary report. Archives of Otolaryngology Head and Neck Surgery 113, 758-761, 1987.

Topalian, S. L., Drake, C. G. and Pardoll, D. M. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Current Opinion in Immunology 24, 207-212, 2012.

van Duijnhoven, F. J., Bueno-De-Mesquita, H. B., Calligaro, M., Jenab, M., Pischon, T., Jansen, E. H., Frohlich, J., Ayyobi, A., Overvad, K., Toft-Petersen, A. P., Tjønneland, A., Hansen, L., Boutron-Ruault, M. C., Clavel-Chapelon, F., Cottet, V., Palli, D., Tagliabue, G., Panico, S., Tumino, R., Vineis, P., Kaaks, R., Teucher, B., Boeing, H., Drogan, D., Trichopoulou, A., Lagiou, P., Dilis, V., Peeters, P. H., Siersema, P. D., Rodríguez, L., González, C. A., Molina-Montes, E., Dorronsoro, M., Tormo, M. J., Barricarte, A., Palmqvist, R., Hallmans, G., Khaw, K. T., Tsilidis, K. K., Crowe, F. L., Chajes, V., Fedirko, V., Rinaldi, S., Norat, T. and Riboli, E. Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition. Gut 60, 1094-1102, 2011.

Vermorken, J. B., Mesia, R., Rivera, F., Remenar, E., Kawecki, A., Rottey, S., Erfan, J., Zabolotnyy, D., Kienzer, H. R., Cupissol, D., Peyrade, F., Benasso, M., Vynnychenko, I., De Raucourt, D., Bokemeyer, C., Schueler, A., Amellal, N. and Hitt, R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. The New England Journal of Medicine 359, 1116-1127, 2008.

Vermorken, J. B. and Specenier, P. Optimal treatment for recurrent/metastatic head and neck cancer. Annals of Oncology 21, vii252–vii261, 2010.

Vigneswaran N. and Williams M. D. Epidemiologic trends in head and neck cancer and aids in diagnosis. Oral and Maxillofacial Surgery Clinics of North America 26, 123-141, 2014.

Wang, G. Z., Zhang, L., Zhao, X. C., Gao, S. H., Qu, L. W., Yu, H., Fang, W. F., Zhou, Y. C., Liang, F., Zhang, C., Huang, Y. C., Liu, Z., Fu, Y. X. and Zhou, G. B. The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy. Nature Communications 10, 1125, 2019a.

Wang, X., Yang, L., Huang, F., Zhang, Q., Liu, S., Ma, L. and You, Z. Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunology Letters 184, 7-14, 2017.
Wang, Z., Aguilar, E. G., Luna, J. I., Dunai, C., Khuat, L. T., Le, C. T., Mirsoian, A., Minnar, C. M., Stoffel, K. M., Sturgill, I. R., Grossenbacher, S. K., Withers, S. S., Rebhun, R. B., Hartigan-O'Connor, D. J., Méndez-Lagares, G., Tarantal, A. F., Isseroff, R. R., Griffith, T. S., Schalper, K. A., Merleev, A., Saha, A., Maverakis, E., Kelly, K., Aljumaily, R., Ibrahimi, S., Mukherjee, S., Machiorlatti, M., Vesely, S. K., Longo, D. L., Blazar, B. R., Canter, R. J., Murphy, W. J. and Monjazeb, A. M. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine 25, 141-151, 2019b.

Winkels, R. M., Heine-Bröring, R. C., van Zutphen, M., van Harten-Gerritsen, S., Kok, D. E., van Duijnhoven, F. J. and Kampman, E. The COLON study: Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that may influence colorectal tumour recurrence, survival and quality of life. Biomed Central Genomics Cancer 14, 374, 2014.

Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R. A., Reed, K., Burke, M. M., Caldwell, A., Kronenberg, S. A., Agunwamba, B. U., Zhang, X., Lowy, I., Inzunza, H. D., Feely, W., Horak, C. E., Hong, Q., Korman, A. J., Wigginton, J. M., Gupta, A. and Sznol, M. Nivolumab plus ipilimumab in advanced melanoma. The New England Journal of Medicine 369, 122-133, 2013.

Woods, R. L., Fox, R. M. and Tattersall, M. H. Methotrexate treatment of squamous-cell head and neck cancers: dose-response evaluation. British Medical Journal 282, 600-602, 1981.

Wu, P., Wu, D., Li, L., Chai, Y. and Huang, J. PD-L1 and Survival in Solid Tumors: A Meta-Analysis. Public Library of Science One 10, e0131403, 2015.

Wu, X., Li, Y., Liu, X., Chen, C., Harrington, S. M., Cao, S., Xie, T., Orzechowski, A., Pham, T., Mansfield, A. S., Yan, Y., Kwon, E. D., Wang, L., Ling, K. and Dong, H. Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy. Heliyon 4, e01039, 2018.

Xia, Y., Shen, S. and Verma, I. M. NF-κB, an active player in human cancers. Cancer Immunology Research 2, 823-830, 2014.
Xie, W. B., Liang, L. H., Wu, K. G., Wang, L. X., He, X., Song, C., Wang, Y. Q. and Li, Y. H. MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC. Cellular Physiology and Biochemistry 46, 654-663, 2018.

Xu-Monette, Z. Y., Zhang, M., Li, J. and Young, K. H. PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response? Frontiers in Immunology 8, 1597, 2017.

Yamada, K., Araki, S., Tamura, M., Sakai, I., Takahashi, Y., Kashihara, H. and Kono, S. Relation of serum total cholesterol, serum triglycerides and fasting plasma glucose to colorectal carcinoma in situ. International Journal of Epidemiology 27, 794-798, 1998.

Yao, H., Wang, H., Li, C., Fang, J. Y. and Xu, J. Cancer Cell-Intrinsic PD-1 and Implications in Combinatorial Immunotherapy. Frontiers in Immunology 9, 1774, 2018.

Zalesin, K. C., Franklin, B. A., Miller, W. M., Peterson, E. D. and McCullough, P. A. Impact of obesity on cardiovascular disease. Medical Clinics of North America 95, 919-937, 2011.

Zandberg, D. P. and Strome, S. E. The role of the PD-L1: PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncology 50, 627-632, 2014.

Zhang, H., Berezov, A., Wang, Q., Zhang, G., Drebin, J., Murali, R. and Greene, M. I. ErbB receptors: from oncogenes to targeted cancer therapies. Journal of Clinical Investigation 117, 2051-2058, 2007.

Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., Guo, J., Huang, Y. H., Fan, C., Ren, S., Sun, Y., Freeman, G. J., Sicinski, P. and Wei, W. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553, 91-95, 2018.

Zhang, Y., Lu, H., Dazin, P. and Kapila, Y. Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin alphav mediate survival signals through focal adhesion kinase. Journal of Biological Chemistry 279, 48342-48349, 2004.

Zimmet, P. Z. and Alberti, K. G. Introduction: Globalization and the non-communicable disease epidemic. Obesity 14, 1-3, 2006.

Zou, W. and Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nature Reviews Immunology 8, 467-477, 2008.