Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response

Abstract

Background Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response. Methods In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response. Results We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. Immune-profiling showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26. Genomic/transcriptomic analyses highlighted thatWnt pathway was one of the potential differences between CT-26 and Colon 26, showing Wnt activity was higher in Colon 26 than CT-26. . Conclusions CT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed “hot tumor” profile with more infiltrated immune cells than Colon 26. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients.

Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response

“…The 4T1 and CT26 models are described to belong to tumors with differential immunoscore level. Indeed, the 4T1 model could be considered as a ‘cold’ phenotype with low response to immunotherapies [65] , despite the CT26 could be considered as a ‘hot’ phenotype with good response to immunotherapies [66] . Altogether these data might participate to explain the immunotherapy response observed in this work and in clinical observations.…”

Targeting thymidine phosphorylase alleviates resistance to dendritic cell immunotherapy in colorectal cancer and promotes antitumor immunity

“…Murine CT-26 cells, similar to human CRC cells, are massively invaded by TAMs and Tregs, which are associated with poor prognosis ( 51 ). In our study, we observed that neither a low dose of TPI nor IMQDC-Ag alone could induce ICD in vivo, whereas combination therapy did.…”

5-Fluorouracil Treatment of CT26 Colon Cancer Is Compromised by Combined Therapy with IMMODIN

“…Secondly, existing pre-clinical models of human CRC that rely on syngeneic subcutaneous grafts are problematic because of increasing evidence that the immune microenvironment in subcutaneous tissue significantly differs from the gastrointestinal tract [ 70 ]. However, as shown by our study, the heterotopic syngeneic CT26 model, in addition to its use as a platform model for evaluating the efficacy of anti-cancer drug combinations, could also be used to assess phenotypic changes in the immune system [ 71 ]. Moreover, the resemblance of the CT26 models to the clinical observations of the response of CRC patients treated with immune checkpoint blockers further supports the relevance of the chosen model.…”