Targeting Interleukin-6 (IL-6) Sensitizes Anti-PD-L1 Treatment in a Colorectal Cancer Preclinical Model
| Autor: | Keer Jin, Rui Zhang, Wenya Li, Jibin Li, Xiaofei Yan, Jian Xu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Male Colorectal cancer medicine.medical_treatment CD8-Positive T-Lymphocytes T-Lymphocytes Regulatory B7-H1 Antigen 03 medical and health sciences Mice Immune system Downregulation and upregulation Clinical Research Antigens CD274 Cell Line Tumor medicine Animals Humans Interleukin 6 Mice Knockout Immunity Cellular Mice Inbred BALB C biology business.industry Interleukin-6 Immunosuppression General Medicine medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis Immune checkpoint Blockade Mice Inbred C57BL Disease Models Animal 030104 developmental biology biology.protein Cancer research Female business Colorectal Neoplasms CD8 |
| Zdroj: | Medical Science Monitor : International Medical Journal of Experimental and Clinical Research |
| ISSN: | 1643-3750 1234-1010 |
| Popis: | BACKGROUND Limited efficacy of immune checkpoint blockades was observed in clinical trials in colorectal (CRC) patients, especially in the microsatellite-stable patients. Interleukin-6 (IL-6) is critical in modeling immune responses in cancers. However, the effects of targeting IL-6 in combination with immune checkpoint blockades is unknown in CRC. MATERIAL AND METHODS In the present study, we investigated the profile of IL-6 expression in tumor tissues of CRC patient and we established CRC mouse models with various IL-6 expression levels using CT26 cells and MC38 cells. Effects of anti-IL-6 and anti-PD-L1 combination treatment were tested in these models. RESULTS A total of 105 CRC patients were included in this study, with 41 (39%) females and 64 (61%) males. Sixty patients showed IL-6 high expression and 45 patients showed IL-6 low expression. The patients with IL-6 high expression tended to have shorter survival (median survival time of 25.5 months) than the patients with IL-6 low expression (median survival time of 46 months, P value=0.013). In the CRC mouse models, tumors with IL-6 overexpression tended to grow faster than the tumors with IL-6 knockout. The numbers of CD8+ T cells and CD4+ T cells were decreased in IL-6 overexpressed tumors. On the contrary, myeloid-derived suppressor cells and regulatory/suppressor T cells were more numerous in tumors with IL-6 overexpression. PD-L1 expression was upregulated in the tumors with IL-6 overexpression. Importantly, an IL-6 blockade reversed the anti-PD-L1 resistance and prolonged tumor-bearing mouse survival. CONCLUSIONS Our study indicates that IL-6 induces strong immunosuppression in the CRC microenvironment by recruiting immunosuppression cells and impairing T cell infiltration. Inhibition of IL-6 enhanced the efficacy of anti-PD-L1 in CRC, providing a novel strategy to overcome anti-PD-L1 resistance in CRC. |
| Databáze: | OpenAIRE |
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