CD11b⁺CTLA4⁺myeloid cells are a key driver of tumor evasion in colorectal cancer

Abstract

BackgroundTumor metastasis is the major cause of death of colorectal cancer (CRC), and metastatic CRC remains incurable in many cases despite great advances in genetic and molecular profiling, and clinical development of numerous drugs, including immune checkpoint inhibitors. Thus, more effective treatments are urgently needed for the patients in clinical settings.MethodsWe used mouse CRC metastasis models that murine Colon26 cells were subcutaneously and intravenously implanted and attempted to elucidate the tumor biological and immunological mechanisms underlying cancer metastasis. Then, we evaluated in vivo antitumor efficacy induced by agents targeting the identified molecular mechanisms using the mouse models. We validated the clinical relevancy of the findings using peripheral blood mononuclear cells obtained from stage IV metastatic CRC patients.ResultsCD11b+CTLA4+ myeloid cells were systemically expanded in the metastatic settings and facilitated tumor progression and metastasis directly via generating lipid droplets in tumor cells and indirectly via inducing immune exhaustion. These events were mediated by IL1B produced via the CTLA4 signaling from the increased myeloid cells. Blocking CTLA4 and IL1B with the specific mAbs significantly suppressed tumor progression and metastasis in the mouse models resistant to anti-PD1 therapy, and the therapeutic efficacy was optimized by blocking cyclooxygenases with aspirin.ConclusionsThe CD11b+CTLA4+ cells are a key driver of tumor evasion, and targeting the CTLA4-IL1B axis could be a promising strategy for treating metastatic CRC. The triple combination regimen with anti-CTLA4/IL1B mAbs and aspirin may be useful in clinical settings.

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

“…These findings indicate that CTLA-4 may regulate the induction and functional state of MDSCs and macrophages [ 69 ]. In accordance, it has been observed that CD11b + CTLA-4 + cells mediated tumor progression via IL-1β production and by CTLA-4 signaling in a mouse model of CRC [ 70 ]. More specifically, Yang and coworkers reported that MDSC-mediated immunosuppression in a murine model of ovarian cancer was significantly reduced upon CTLA-4 blockade, which was largely attributed to a reduction in arginase I activity by these cells [ 71 ].…”

Clinical and Immunological Effects of p53-Targeting Vaccines

“…MDSCs are pathologically activated myeloid progenitors and immature myeloid cells with potent immunosuppressive activity ( Hegde et al, 2021 ; Veglia et al, 2021 ). A number of studies have demonstrated that MDSCs are implicated in T cell suppression and are closely associated with poor clinical outcomes in cancer ( Wang et al, 2020b ; Imazeki et al, 2021 ). Mouse experiment also demonstrated that MDSC depletion with antibodies or different compounds could substantially improve anti-tumor immune responses to exert anti-tumor effects ( Gabrilovich et al, 2012 ).…”

Prognostic Assessment of Oxidative Stress-Related Genes in Colorectal Cancer and New Insights into Tumor Immunity

“…CYBA can induce familial colorectal cancer by interfering with the integrity of intestinal barrier [ 36 ]. IL-1B, as a member of the interleukin family, is closely related to tumor immunity [ 37 ]. SOD2 contributes to the chemical resistance of colorectal cancer [ 38 ], and according to research, MAPK8 can promote the progression of colorectal cancer [ 39 ].…”