腫瘤微環境由多種不同細胞群組成，並且調控腫瘤進展。其中腫瘤微環境中的多種免疫抑制途徑會被活化，並透過抑制抗腫瘤免疫來促進腫瘤生長。因此，抑制這些免疫抑制途徑以增強抗腫瘤免疫，被視為一種具有潛力的癌症治療策略。極光激酶A為一種絲胺酸/蘇胺酸激酶，並在中心體功能、細胞有絲分裂和染色體穩定性方面扮演重要角色。在過往研究中發現，腫瘤中有較高極光激酶A表現的病患其預後較差。因此，在癌症的治療中使用極光激酶A抑制劑被認為是具有發展性的治療手段。然而，許多針對極光激酶A設計的小分抑制劑在臨床二期及三期的實驗中並未獲得成功。近年來有研究發現在不同癌症中抑制某些致癌蛋白也同時會抑制抗腫瘤免疫。然而，我們對腫瘤細胞內極光激酶A在腫瘤免疫中所扮演角色目前尚未了解透徹。在本研究中，我們發現在大腸直腸癌病患中，腫瘤內有較低淋巴細胞浸潤的情況下極光激酶A表達量較高則預後較差，相反的，在較高淋巴細胞浸潤的情況下極光激酶A達量較高則預後較好。此外，過去文獻報導小鼠大腸直腸癌細胞株CT26所形成腫瘤為高度免疫細胞浸潤之免疫熱腫瘤，且於CT26細胞內抑制極光激酶A表現，在免疫健全鼠中能夠過抑制CD8+ T 細胞的浸潤及毒殺能力來促進腫瘤生長。我們同時也發現極光激酶A能透過其激酶的活性在大腸直腸癌細胞中負調控白介素-16（IL-16）的表現。於極光激酶A被抑制的CT26腫瘤中，使用白細胞介素-16中和性抗體能透過促進CD8+ T 細胞的毒殺能力來制腫瘤生長。在此研究中，我們發現在免疫熱腫瘤中癌細胞內的極光激酶A能透過抑制白細胞介素-16的表現來促進抗腫瘤免疫。當腫瘤中免疫細胞浸潤多的狀況下，抑制的極光激酶A雖然能抑制癌細胞生長也抑制抗腫瘤免疫。因此，在腫瘤中有高度免疫浸潤的話，共同抑制極光激酶A以及白細胞介素-16會是更好的治療方式。

The tumor microenvironment (TME) comprises various cell populations that contribute to tumor progression, with several immunosuppressive pathways promoting tumor growth by inhibiting antitumor immunity. Targeting these pathways to enhance antitumor immunity is regarded as a potential cancer treatment strategy. Aurora-A kinase, a serine/threonine kinase essential for centrosome function, cell mitosis, and chromosome stability, is often overexpressed in cancers with poor prognosis. Despite its promising potential as a therapeutic target, inhibitors of Aurora-A kinase have shown limited success in clinical trials. Recent studies suggest that inhibiting certain oncoproteins might also diminish antitumor immunity. However, the role of tumor-intrinsic Aurora-A kinase in regulating tumor immunity in the TME is not fully understood. In this study, we found that colorectal cancer (CRC) patients with lower lymphocyte infiltration and higher Aurora-A expression in the tumors correlate with worse prognosis. In contrast, the CRC patients with higher lymphocyte infiltration and higher Aurora-A expression in the tumors correlate with better prognosis. Specifically, in the CT26 mouse tumor model, an immune-hot tumor type, Aurora-A knockdown promoted tumor growth by inhibiting CD8+ T cell infiltration and activity. In addition, we discovered that Aurora-A kinase negatively regulates interleukin-16 (IL-16) expression in CRC cells in a kinase-dependent manner. Neutralizing IL-16 reversed the tumor-promoting effects of Aurora-A knockdown in these models. Our findings indicate that inhibition of tumor-intrinsic Aurora-A can impair antitumor immunity by enhancing IL-16 production. Therefore, in tumors with high immune cell infiltration, Aurora-A inhibition may concurrently suppress cancer cell growth and reduce antitumor immunity. We propose that a combined approach, inhibiting both Aurora-A kinase and IL-16, could be a more effective therapeutic strategy in such tumors.

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