P2.04-04 Expression of Intratumoral Programmed Cell Death-Ligand 1 (PD-L1) and Intratumoral CD4+T Cell, CD8+T Cell and FOXP3+T Cell in Lung Cancer

Overexpression of PD-1 and PD-L1 induces immune evasion by cancer cells. Blockade of this immune checkpoint could reverse the tumor immune system and activate the anti-cancer response. Nivolumab and pembrolizumab, anti-PD-1 antibodies, were recently approved for the treatment of advanced NSCLC. A PD-L1 positive expression status by immunohistochemistry (IHC) has been associated with a favorable response. However responses to these drugs are limited, with the objective response rate ranging between 20%-30%. These results suggest that individual tumor microenvironments vary according to the immune evasion process of each cancer tissue. Consequently, the introduction of biomarkers, which predict the responders to the immune checkpoint blockades are necessary in clinical practice. FOXP3+CD4+ regulatory T cells recognizing tumor-specific shared antigens maintain the immunological self-tolerance and suppress the activation of T cells in cancer tissue. Moreover, anti-CTLA-4 monoclonal antibody therapy reduces FOXP3+CD4+ expression in cancer tissue. However, the precise conditions and diagnostic value of these immunological factors remain uncertain and specific biomarkers predictive of response have not yet been identified. PD-L1, CD4, CD8 and FOXP3 expression in tumor cells and tumor infiltrating lymphocytes (TILs) were examined by IHC in 45 cases (including 32 cases of adenocarcinoma and 13 cases of squamous cell carcinoma) with advanced lung cancer treated with nivolumab or pembrolizumab. Histologic subtypes, tumor stage and other clinicopathologic conditions were compared with the level of their expression. Expression of PD-L1 expression in tumor cells was detected in 75.6% of the cases. The objective response rate was 46.7%, and it was significantly correlated PD-L1 positivity with CD8 TILs (p<0.0001). Eleven cases having driver gene mutations did not show a tendency towards favorable response. Cases with PD-L1 overexpression showed consistently dense CD8+ TILs, even in subgroup analyses according to histological subtype, stage, age and smoking status. In cancer-associated stroma, CD4+ cells and FOXP3+ positive cells were detected, and cases with PD-L1-, low CD8+, and FOXP3+ status were also detected. Overexpression of PD-L1 with CD8+ TILs was associated with a favorable response to treatment with nivolumab and pembrolizumab. In contrast, PD-L1- with low CD8+ TILs and FOXP3+ TILs was not associated with favorable response. Therefore, assessment of PD-L1, CD8+ TILs and FOXP3+ TILs by IHC may be valuable for predicting response to treatment with nivolumab and pembrolizumab. PD-L1-and CD8+ TILs and FOXP3+ TILs may be indicative of a combination with other therapeutic agents. Investigation of novel combinations of immunotherapy according to individual tumor microenvironments is warranted.