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研究生：	曾彥誠 Tseng, Yen-Cheng
論文名稱：	阻斷IL-33和ST2L的中和抗體能增加肺癌中抗腫瘤免疫反應 Blockage of IL-33 and ST2L by neutralizing antibodies increases anti-tumor immune responses in lung cancer
指導教授：	張志鵬 Chang, Chih-Peng
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	89
中文關鍵詞：	肺癌、順鉑、介白素33 、第二穿膜型抑制致瘤性受體、腫瘤微環境
外文關鍵詞：	Lung cancer, Cisplatin, Interleukin-33, Transmembrane form suppression of tumorigenicity-2, Antibody drug, Tumor microenvironment
相關次數：	點閱：105 下載：0
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肺癌是目前世界上最常見且致死率高的癌症。在治療上，化療藥物誘導肺癌患者腫瘤免疫逃脫，是臨床上新出現的一個問題。因此，發展出針對腫瘤免疫逃脫的治療策略，對於肺癌治療至關重要。介白素33 (interleukin-33)是在腫瘤微環境中被發現的細胞激素，且能與第二穿膜型抑制致瘤性受體 (transmembrane form suppression of tumorigenicity-2, ST2L)專一性的結合。IL-33/ST2L訊息傳遞已被報導，會透過抑制腫瘤微環境中的抗腫瘤免疫反應，來促進肺癌的進展。阻斷IL-33和ST2L之間的交互作用可能有益於治療肺癌。在本研究中，我們透過與偉喬生技公司的合作，針對IL-33和ST2L生產了老鼠的中和性單株抗體。我們發現雖然這些中和抗體並不會影響肺癌細胞 (Lewis lung carcinoma, LLC)在體外的生長與死亡，但這些抗體可以顯著減緩小鼠中LLC腫瘤的生長。值得注意的是，透過組織免疫螢光染色的實驗可以發現，在抗體治療過的LLC腫瘤中，CD8+ T細胞浸潤到腫瘤內的數量增加，而Foxp3+調節T細胞(Treg)和M2型巨噬細胞的浸潤則相對減少，且PD-L1在腫瘤中的表現量也因為抗體的治療而降低。另外，由體外細胞培養實驗也顯示，利用中和性抗體阻斷IL-33和ST2L的訊息，能夠分別抑制Foxp3+ 調節T細胞和M2型巨噬細胞從初始T細胞和骨髓衍生巨噬細胞的分化，且同樣能減少PD-L1在肺癌細胞上的表現。這些結果與在抗體治療LCC腫瘤小鼠身上所發現的現象一致。順鉑(cisplatin)是治療晚期肺癌患者的一線化療用藥，有趣的是，我們發現由細胞壞死所釋放的IL-33，在經過順鉑處理的肺癌細胞及帶有LCC腫瘤小鼠中都增加了。給予IL-33和ST2L中和性抗體後，能夠增強LCC腫瘤小鼠中CD8+ T細胞活性，以及提升順鉑的抗腫瘤功效。綜合上述，我們證實利用自家生產的單株抗體來阻斷IL-33 / ST2L訊息傳遞，能增加肺癌中抗腫瘤免疫反應。靶向IL-33 / ST2L軸能作為肺癌治療中，減輕因化療藥物所引起腫瘤免疫逃脫的新策略。

Lung cancer is the first common and the leading cause of cancer-related mortality around the world. In clinical, chemotherapeutics-mediated tumor immunoevasion is an emerging problem to reduce the therapeutic efficacy in lung cancer patients. Thus, development of a promising therapeutic strategy against immunoevasion is critical for lung cancer therapy. Interleukin-33 (IL-33) is one of the cytokines found in the tumor microenvironment (TME) and can specifically bind with transmembrane form suppression of tumorigenicity-2 (ST2L). IL-33/ST2L signaling has been revealed to facilitate lung cancer progression partly through suppressing anti-tumor immunity in the TME. Blocking the interaction between IL-33 and ST2L may be beneficial for treating lung cancer. Here, we cooperated with Leadgene Biomedical, Inc. to generate mouse monoclonal antibodies against IL-33 and ST2L. We found that neutralizing antibodies against IL-33 and ST2L do not cause Lewis lung carcinoma (LLC) cell growth inhibition and death directly, but administration of these antibodies can significantly attenuate LLC tumor growth in mice. Notably, increased infiltration of CD8+ T cells while decreased infiltration of Foxp3+ Tregs and M2 macrophages, as well as reduced PD-L1-expressing LLC cells, were noticed in antibodies-treated LLC tumors by tissue immunofluorescence staining. Consistent with these findings in LCC-bearing mice, our data showed that blockage of IL-33/ST2L signaling by neutralizing antibodies is able to inhibit differentiation of Foxp3+ Tregs and M2 macrophages from naive T cells and bone marrow-derived macrophages, respectively, and can also reduce PD-L1 expression in LLC cells. Cisplatin is one of the first-line chemotherapy drug for advanced lung cancer patients. Interestingly, we demonstrated that the necrotic release of IL-33 was increased in both cisplatin-treated LLC cells and LLC-bearing mice. Treatment of neutralizing antibodies against IL-33 and ST2L is able to enhance CD8+ T cell activity as well as anti-tumor efficacy of cisplatin in LLC-bearing mice. All above, our findings suggest that blockage of IL-33/ST2L by our in-house-generated monoclonal antibodies can increase anti-tumor immunity against lung cancer. Targeting IL-33/ST2L axis may serve as a novel strategy to reduce chemotherapy-mediated tumor immunoevasion in lung cancer therapy.

中文摘要	I
Abstract III
Acknowledgement	V
Table of Contents VI
Abbreviations IX
I. Introduction	1
1. Lung cancer	1
1.1 Etiology of lung cancer 1
1.1.1 Tobacco smoking 1
1.1.2 Occupational and environmental exposures 2
1.1.3 Genetic factors 3
1.2 Histological classification of lung cancer 4
1.2.1 Small cell lung cancer (SCLC) 4
1.2.2 Non-small cell lung cancer (NSCLC) 5
1.3 Treatment of lung cancer 5
1.3.1 Chemotherapy-mediated immunoevasion 6
1.3.2 Cisplatin 7
2. Tumor microenvironment and immunosuppression 7
2.1 M2 macrophages 8
2.2 Regulatory T cells 8
2.3 Myeloid-derived suppressor cells 9
3. IL-33 and ST2L signaling 10
3.1 IL-33 and ST2L 10
3.2 IL-33/ST2L signals in lung tumorigenesis 11
II. Objective and Specific Aims	13
III. Materials and Methods 14
1. Materials 14
1.1 Animal 14
1.2 Cell culture 14
1.3 Antibodies 15
1.4 Specific primer sequences 18
1.5 Reagents 18
2. Methods 24
2.1 LLC-bearing mouse model 24
2.2 Flow cytometry 24
2.3 Primary splenocyte isolation and Foxp3+ regulatory T cell (Treg) differentiation assay 25
2.4 Primary BMDM isolation and M2 macrophages polarization assay 26
2.5 Cellular RNA extraction, RT-PCR and qPCR analysis 26
2.6 Western blotting 26
2.7 Enzyme-linked immunosorbent assay (ELISA) 27
2.8 Lactate dehydrogenase (LDH) releasing assay	27
2.9 WST-1 assay	27
2.10 Antibody neutralization assay 28
2.11 IL-33-mediated NF-κB activation assay 28
2.12 Hematoxylin and eosin (H&E) histopathological staining.	29
2.13 Immunofluorescence assay (IFA) 29
2.14 Immunohistochemistry assay (IHC) 29
2.15 Statistical analysis 30
IV. Results 31
1. Increased expression of IL-33 and ST2L is observed in mouse lung tumors. 31
2. Monoclonal α-IL-33 and α-ST2L antibodies can block the binding and signaling of IL-33. 31
3. Blockage of IL-33/ST2L signaling by neutralizing antibodies inhibits LLC tumor growth in mice. 32
4. Blockage of IL-33/ST2L signaling by neutralizing antibodies reduces immunosuppressive responses in TME. 33
5. Blockage of IL-33/ST2L signaling by neutralizing antibodies inhibits IL-33-induced Foxp3+Treg and M2 macrophage polarization. 34
6. IL-33 and ST2L are up-regulated in cisplatin-treated LLC cells and tumors. 35
7. Blockage of IL-33/ST2L signaling by neutralizing antibodies enhances anti-tumor efficacy of cisplatin. 35
V. Conclusions 37
VI. Discussion 38
Blockage of IL-33/ST2L signaling promotes both anti-tumor immune response and tumor growth inhibition. 38
Blockage of IL-33/ST2L signaling does not show a beneficial effect on lung tumor metastasis. 39
The source of IL-33 in TME. 40
Intrinsic IL-33 may be critical for macrophage phenotype programming. 41
Cisplatin treatment upregulates the mRNA expression and necrotic release of IL-33 in LLC cells and tumors. 42
Our in-house generated monoclonal α-IL-33 and α-ST2L antibodies are potential to improve chemotherapeutic-induced tumor immunoevasion. 43
VII. References	45
VIII. Figures 60
Figure 1. The expression of IL-33 and ST2L is increased in LLC tumors. 61
Figure 2. The growth of LLC tumors is attenuated in IL-33-/- mice. 62
Figure 3. Monoclonal α-IL-33 and α-ST2L antibodies can block binding and signaling of IL-33.	64
Figure 4. Monoclonal α-IL-33 and α-ST2L antibodies do not cause LLC cell growth inhibition and cell death. 67
Figure 5. Monoclonal α-IL-33 and α-ST2L antibodies do not cause significant toxicity in mice. 69
Figure 6. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies suppresses LLC tumor growth. 70
Figure 7. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies is not able to inhibit metastasis of LLC.	71
Figure 8. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies reduces immunosuppressive response in the TME. 74
Figure 9. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies inhibits IL-33-induced PD-L1 expression on LLC cells and tumors. 76
Figure 10. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies inhibits IL-33-promoted CD4+Foxp3+ Tregs differentiation. 77
Figure 11. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies inhibits IL-33-promoted M2 macrophage polarization. 79
Figure 12. Cisplatin treatment promotes IL-33 and ST2L expression in LLC cells and tumors. 81
Figure 13. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies enhances the anti-tumor effect of cisplatin. 83
Figure 15. Blockage of IL-33/ST2L by monoclonal α-IL-33 and α-ST2L antibodies suppresses lung tumor growth via promoting anti-tumor immune response in the TME. 87
IX. Appendix 88
Appendix 1. IL-33 involves in IFN-γ and IL-13-mediated macrophage polarization. 88
Appendix 2. Cisplatin treatment causes LDH release from LLC cells. 89

                                    

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