Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
Open Access
- 18 January 2021
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 9 (1), e001895
- https://doi.org/10.1136/jitc-2020-001895
Abstract
Background Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models. Methods The expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors. Results Evaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors. Conclusions IL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.Keywords
Funding Information
- Provincial Natural Science Foundation Outstanding Youth Project (JQ2019H003)
- National Natural Science Foundation of China (81703000, 81872427, 81872435)
- Central guides local science and technology development project (ZY16A07)
- National Youth Talent Support Program
- National Key R&D Program of China (2018YFC1313300)
- Nn10 Excellent Discipline Construction Program (Hepatobiliary and Pancreatic Tumor 2017)
- Applied Technology Research and Development Program of Heilongjiang Province (GA19C002)
- China Postdoctoral Science Foundation Grant (2018M631956)
- Haiyan Research Fund of HMU Cancer Hospital (JJQN2020-07)
- Heilongjiang Postdoctoral Fund (LBH-Z17162)
This publication has 51 references indexed in Scilit:
- miR-15b and miR-17 Are Tumor-derived Plasma MicroRNAs Dysregulated in Colorectal NeoplasiaAnnals of Surgery, 2015
- Colitis-accelerated colorectal cancer and metabolic dysregulation in a mouse modelCarcinogenesis: Integrative Cancer Research, 2013
- Dual biological effects of the cytokines interleukin-10 and interferon-γCancer Immunology, Immunotherapy, 2011
- Clinical Impact of Different Classes of Infiltrating T Cytotoxic and Helper Cells (Th1, Th2, Treg, Th17) in Patients with Colorectal CancerCancer Research, 2011
- Immune infiltration in human tumors: a prognostic factor that should not be ignoredOncogene, 2009
- High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomasGut, 2008
- NRF-1 is the major transcription factor regulating the expression of the human TOMM34 geneBiochemistry and Cell Biology, 2008
- Enhanced transduction of colonic cell lines in vitroand the inflamed colon in mice by viral vectors, derived from adeno-associated virus serotype 2, using virus-microbead conjugates bearing lectinBMC Biotechnology, 2007
- Tumor Infiltrating T Lymphocytes in Colorectal CancerAnnals of Surgery, 2006
- Reverse of NK cytolysis resistance of type II cytokine predominant-human tumor cellsInternational Immunopharmacology, 2006