Abstract
PurposeDeficient mismatch repair (dMMR) is an established biomarker for the response to the programmed cell death (PD)-1 inhibitors in metastatic colorectal cancer (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 from 28% to 52%. We aimed to explore the additional predictive biomarkers associated with response to anti-PD-1 immunotherapy in patients with dMMR mCRC.MethodsThis multicenter cohort study enrolled patients with dMMR mCRC receiving anti-PD-1 immunotherapy at the Sixth Affiliated Hospital of Sun Yat-sen University and Sun Yat-sen University Cancer Center between December 2016 and December 2019. The total information of 20 peripheral blood biomarkers, including T cells (frequency of CD4+ T cell, frequency of CD8+ T cell, and ratio of CD4+/CD8+), carcinoembryonic antigen (CEA), inflammatory markers, and lipid metabolism markers, was collected. The association between response or survival and peripheral blood parameters was analyzed.ResultsAmong the tested parameters, the ratio of CD4+/CD8+ and frequency of CD4+ T cell were significantly associated with PFS (p = 0.023, p = 0.012) and overall survival (OS; p = 0.027, p = 0.019) in a univariate analysis. A lower level of CD4+/CD8+ ratio or frequency of CD4+ T cell showed a significant association with better overall response rates (ORRs; p = 0.03, p = 0.01). The 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).ConclusionThis study indicated that the ratio of CD4+/CD8+ and the frequency of CD4+ T cell might be crucial independent biomarkers within dMMR mCRC to better identify patients for anti-PD-1 immunotherapy. If validated in prospective clinical trials, the ratio of CD4+/CD8+ and the frequency of CD4+ T cell might aid in guiding the treatment of PD-1 inhibitors among patients with dMMR mCRC.
Highlights
Colorectal cancer (CRC) is the fourth most common cause of cancer-related death globally, and there is an increasing incidence of CRC [1, 2]
Promising efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy has been reported in locally advanced colon cancer with deficient mismatch repair (dMMR) tumors [4], the overall response (OR) rates (ORRs) in microsatellite instability-high (MSI-H) metastatic CRC (mCRC) patients are variable from 28% to 52% [3, 5, 6], which were likely attributed to tumor heterogeneity
A total of 41 mCRC patients with dMMR tumors were identified to be treated with programmed cell death (PD)-1 inhibitors
Summary
Colorectal cancer (CRC) is the fourth most common cause of cancer-related death globally, and there is an increasing incidence of CRC [1, 2]. Tumor-infiltrating lymphocytes (frequency of CD8+ T cells) mainly contribute to the antitumor immune response and are a reliable prognostic indicator for CRC [8, 9]. It is not an optimal predictor for anti-PD-1 immunotherapy. Lipid metabolism has been demonstrated to play an important role in the promotion of migration [16] and invasion [17] and be related to tumor immune milieu [18] It remains unclear whether the peripheral blood profiling could detect the responses to anti-PD-1 immunotherapy in MSI-H mCRC patients. This multicenter study analyzed 41 mCRC patients with dMMR tumors to investigate the potential association between peripheral biomarkers with response to anti-PD-1 immunotherapy
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