<i>TP53, STK11</i> , and <i>EGFR</i> Mutations Predict Tumor Immune Profile and the Response to Anti–PD-1 in Lung Adenocarcinoma

<b>Purpose:</b> By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed.<b>Experimental Design:</b> We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained.<b>Results:</b> We showed that distinct combinations of <i>STK11, EGFR</i>, and <i>TP53</i> mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of <i>TP53</i> mutations without co-occurring <i>STK11</i> or <i>EGFR</i> alterations (<i>TP53</i>-mut/<i>STK11</i>-<i>EGFR</i>-WT), independently of <i>KRAS</i> mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16-0.63, <i>P</i> < 0.001) was observed in anti-PD-1-treated patients harboring <i>TP53</i>-mut/<i>STK11</i>-<i>EGFR</i>-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.<b>Conclusions:</b> Our study reveals that different combinations of <i>TP53, EGFR</i>, and <i>STK11</i> mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. <i>Clin Cancer Res; 24(22); 5710-23. ©2018 AACR</i>.