Clinical relevance of PD-L1 expression and CD8+T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer

Objectives: EGFR-mutated or ALK-rearranged non-small cell lung cancer (NSCLC) often showed unfavorable clinical benefit to checkpoint inhibitors (CPIs). However, few reports exist with integrated analysis, to interpret the underlying mechanism of poor response to PD-1/PD-L1 inhibitors. We have retrospectively analyzed the tumor microenvironment (TME) based on tumor PD-L1 expression and CD8 + T cells infiltration in patients with EGFR mutations and ALK rearrangements, and the prognostic value of TME subtypes on overall survival (OS). Materials and methods: Tumor samples from 715 patients with lung cancer were retrospectively collected at Guangdong Lung Cancer Institute. Tumoral PD-L1 expression (N = 715) and CD8 + T cells infiltration (N = 658) was determined by immunohistochemistry (IHC), based on which TME was categorized into four different subtypes: PD-L1 +/CD8 +, PD-L1-/CD8 +, PD-L1+/CD8-, PD-L1-/CD8-. Proportion of four TME subtypes was determined, and overall survival with PD-L1 expression and TME was analyzed. Results: In patients with EGFR mutations or ALK rearrangements, proportion of PD-L1 +/CD8 + tumors was the lowest (5.0%, 17/342), and that of PD-L1-/CD8- tumors was the highest (63.5%, 217/342). In patients with wild-type EGFR and ALK, 14.2% (45/316) tumors were PD-Ll +/CD8 + and 50.3% (159/316) tumors were PD-L1-/CD8- (P < 0.001). Median OS of EGFR-mutated or ALK-rearranged lung cancer was 78.6 months in PD-Ll positive group and 93.4 months in PD-Ll negative group (HR 0.47, 95%CI 0.23-0.76, P = 0.005). PD-L1+/ CD8 + group exhibited the shortest OS, with 44.3 months, but is likely to respond to CPIs. The PD-L1-/CD8 + group exhibited the longest OS but is unlikely to respond to CPIs. Conclusion: Patients with EGFR mutations or ALK rearrangements exhibited lower PD-Ll and CD8 co-expression level in TME, which could be responsible for poor response to CPIs. PD-Ll and CD8 co-expression in EGFR-mutated or ALK-rearranged lung cancer is a biomarker for poor prognosis with shorter OS.