Journal
MEDICAL SCIENCE MONITOR
Volume 24, Issue -, Pages 5501-5508Publisher
INT SCIENTIFIC LITERATURE, INC
DOI: 10.12659/MSM.907439
Keywords
Antigens, CD274; Colorectal Neoplasms, Hereditary Nonpolyposis; Immunity, Cellular; Interleukin-6
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Funding
- National Natural Science Fund from the National Natural Science Foundation of China [81672427]
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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/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 an- ti-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-PDLl in CRC, providing a novel strategy to overcome anti-PD-L1 resistance in CRC.
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