1. State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China;
2. Department of the VIP region, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China;
3. Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China;
4. Department of the Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Centre, Guangzhou, 510000, PR China.
* Equal contributors.
Clinical outcomes of checkpoint blockade immunotherapy on colorectal cancer (CRC) are influenced by mismatch repair (MMR) gene status, which is associated with distinct tumor immune infiltrates and systemic inflammatory response status. However, the prognostic value of PD-L1 expression and the systemic inflammatory response for patients with MMR deficiency has not been fully investigated. In this study, we examined the association of systemic inflammatory markers, PD-1/PD-L1 pathway expression, microsatellite instability (MSI) status, and clinicopathological characteristics of CRC with patient survival between MMR-deficient (dMMR) group (N=168) and MMR-proficient (pMMR) group (N=169). We found a large proportion of dMMR CRC patients displayed increased level of systemic inflammatory markers such as C-reactive protein, Neutrophil/Lymphocyte Ratio (NLR), Glasgow Prognostic Score (GPS), and low expression of PD-L1 in tumor stroma. Several systemic inflammatory markers were associated with AJCC stage only in dMMR patients. Similarly, Tumor infiltrating lymphocyte (TIL) PD-L1 or stroma PD-L1 expression was associated with AJCC stage only in dMMR patients. Circulating serum lymphocytes and TIL PD-L1 expression are both independent prognosis predictors for CRC patients. Overall, we found that dMMR CRC displayed a comprehensively distinct tumor immune microenvironment and systemic inflammatory response makers. PD-L1 expression at different location has different impacts on CRC patient survival, and the TIL PD-L1 expression might be a potential predictor for dMMR CRC patient response to anti-PD-1 therapy.
Keywords: PD-L1, PD-1, tumor infiltrating lymphocytes, colorectal cancer, immunotherapy, predictor