Association of Peripheral Blood Biomarkers with Response to anti-PD-1 Immunotherapy for Patients with dMMR Metastatic Colorectal Cancer: A Multicenter Cohort Study

Abstract Background: Mismatch repair deficient (dMMR) is an established biomarker for response to anti-PD-1 immunotherapy in metastatic colorectal carcinoma (mCRC). Although patients with dMMR mCRC could achieve a high incidence of disease control and favorable progression-free survival (PFS), reported response rates to PD-1 inhibitors are variable with 28%–52%, indicating that additional predictive biomarkers are warranted.Methods: This multicenter cohort study enrolled patients with dMMR mCRC receiving anti-PD-1 immunotherapy at Sun Yat-sen University, the Sixth Affiliated Hospital and Sun Yat-sen University Cancer Center between December, 2016 to December, 2019. A total of 20 peripheral blood biomarkers, including T cells (frequency of CD4+ T cell, frequency of CD8+ T cell, ratio of CD4+/CD8+), carcinoembryonic antigen (CEA), inflammatory markers and lipid metabolism markers. The association between response or survival and peripheral blood parameters was analyzed. Results: Among tested parameters, ratio of CD4+/CD8+, frequency of CD4+ T cell was significantly associated with PFS (P=0.023, P=0.012) and OS (P=0.027, P=0.019) in univariate analysis. Lower level of CD4+/CD8+ ratio or frequency of CD4+ T cell showed significant association with better overall response rates (ORR; P = 0.03, P=0.01). Ratio of CD4+/CD8+, and frequency of CD4+ T cell maintained significance in multivariate Cox model for PFS (HR=9.23, P=0.004; HR=4.83, P=0.02) and OS (HR=15.22, P=0.009; HR=16.21, P=0.025). Conclusions: Ratio of CD4+/CD8+ and frequency of CD4+ T cell might be crucial independent biomarkers within dMMR mCRC to better identify patients for response to PD-1 inhibitors. If validated in prospective clinical trials, ratio of CD4+/CD8+ and frequency of CD4+ T cell might provide aid in guiding the treatment of PD-1 inhibitors in dMMR mCRC.