CRP and soluble CTLA4 are determinants of anti-PD1 resistance in gastrointestinal cancer
Kotoe Oshima1,2, Hirokazu Shoji1, Narikazu Boku1,3
1Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital Tokyo 104-0045, Japan.
Abstract:
Targeting immune inhibitory checkpoint (IC) pathways have attracted great attention as a promising strategy for treating gastrointestinal (GI) cancer. However, the therapeutic efficacy is low in most cases, and little progress has been made in establishing biomarkers that predict the possible responses, and combination regimens that enhance the therapeutic efficacy. As a predictive biomarker, soluble forms of IC molecules have been recently highlighted. However, little is known about which IC molecules is most critically associated with the treatment resistance, and also about the biological and immunological roles of the IC molecules in GI cancer. In this study, we analyzed sera obtained from advanced gastric cancer patients before and one month after treatment with anti-PD1 nivolumab for soluble IC molecules by ELISA. We found that decrease of soluble CTLA4 (sCTLA4) at posttreatment were significantly associated with a better prognosis, and combination with low level of CRP at posttreatment more clearly defined anti-PD1 responders with long-term survival. Indeed, in the in vitro setting, CRP stimulation upregulated CTLA4 expression in tumor cells followed by generation of sCTLA4 that suppressed CTL induction, and simultaneously conferred high self-renewal and invasive abilities on the tumor cells accompanied by increase of EMT-related gene expressions. In the in vivo setting, CRP injection elevated sCTLA4 level in sera of mouse tumor metastasis models, leading to failure of anti-PD1 therapy. However, treatment with anti-CTLA4 mAb or a PPARγ agonist that can reduce in vivo CRP successfully elicited anti-tumor efficacy in the anti-PD1 resistant models. These suggest that targeting CRP and sCTLA4 may be a promising strategy for improving clinical outcomes in the treatments, including anti-PD1 therapy, of GI cancer.
Insights
Researchers found that a decrease in soluble CTLA-4 (sCTLA-4) after nivolumab treatment predicts better outcomes in gastric cancer. Targeting C-reactive protein (CRP) and sCTLA-4 may improve immunotherapy effectiveness.
Area of Science:
- Immunotherapy
- Gastrointestinal Oncology
- Biomarker Discovery
Background:
- Immune checkpoint (IC) inhibitors show promise for gastrointestinal (GI) cancer but have low efficacy and lack predictive biomarkers.
- Soluble forms of IC molecules are emerging as potential biomarkers, but their role in GI cancer treatment resistance is unclear.
- Understanding the biological and immunological functions of IC molecules is crucial for improving cancer therapy.
Purpose of the Study:
- To investigate the association of soluble IC molecules with treatment response in advanced gastric cancer patients.
- To elucidate the biological and immunological roles of C-reactive protein (CRP) and soluble CTLA-4 (sCTLA-4) in anti-PD-1 therapy resistance.
- To explore novel therapeutic strategies targeting CRP and sCTLA-4 to enhance anti-cancer efficacy.
Main Methods:
- ELISA analysis of sera from advanced gastric cancer patients before and after anti-PD-1 (nivolumab) treatment to measure soluble IC molecules.
- In vitro experiments assessing the effects of CRP stimulation on tumor cells, sCTLA-4 generation, and T cell induction.
- In vivo studies using mouse tumor metastasis models to evaluate the impact of CRP on anti-PD-1 therapy and test anti-CTLA-4 or PPARγ agonist treatments.
Main Results:
- A decrease in sCTLA-4 post-treatment correlated significantly with better prognosis in gastric cancer patients receiving nivolumab.
- Low C-reactive protein (CRP) levels combined with decreased sCTLA-4 post-treatment identified patients with long-term survival.
- In vitro and in vivo studies demonstrated that CRP upregulates CTLA-4, increases sCTLA-4, suppresses T cell responses, promotes tumor cell self-renewal and EMT, and confers resistance to anti-PD-1 therapy.
Conclusions:
- Soluble CTLA-4 (sCTLA-4) is a potential predictive biomarker for anti-PD-1 therapy response in GI cancer.
- CRP plays a critical role in promoting treatment resistance by upregulating CTLA-4 and sCTLA-4, and enhancing tumor aggressiveness.
- Targeting CRP and sCTLA-4, potentially through anti-CTLA-4 antibodies or PPARγ agonists, offers a promising strategy to overcome resistance and improve outcomes in GI cancer immunotherapy.
