Abstract
BackgroundImmune 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.MethodsIn 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.ResultsWe 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. .ConclusionsCT-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.
Highlights
Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies
CT-26 tumor-bearing mice are more sensitive to anti-PD-1 checkpoint blockade than Colon 26 tumor-bearing mice, while both tumor models are sensitive to anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade To investigate the sensitivity of various preclinical tumor models to immune checkpoint inhibitors, anti-PD-1 monoclonal antibody was tested across 23 different syngeneic tumor mouse models on C57BL/6, BALB/ c and DBA/2 genetic background mice (Fig. 1A)
We found that anti-PD-1 treatment induced higher growth rate inhibition (GRI) in CT-26 tumor bearing mice than Colon 26, both tumors are murine colorectal carcinoma derived from BALB/c mice (Fig. 1B)
Summary
Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. With the recent focus on immune checkpoint blockades (ICB), is a revolutionary approach and has shown great clinical benefit in multiple tumor types with an intent to “cure.” ICB therapies, such as anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) antibodies, have clinical response rates in the range 10–35% as single agents [1], and the anti-tumor response is not sufficient in many patients and responses are more common in specific tumor types. Understanding how anti-CTLA-4 and anti-PD-1 checkpoint blockade therapies work will be critical for effectively combining them with other anti-cancer therapeutic approaches such as immune-, radio-, chemo- and targeted therapy to improve overall response rate [2]. Multiple studies have found a positive correlation between tumoral PD-L1 expression and anti-PD-1 response or overall survival in some tumor types [3] These evidence suggest that presence of target cells and expression of target molecules of ICB in tumors are the key factors to determine treatment response
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