Abstract 456: Defined co-mutation subgroups of KRAS-mutated NSCLC display distinct immune profiles

Abstract

Abstract Traditional pathological divisions of lung cancer are giving rise to molecular classifications that identify unique drivers of tumor malignancy. Of these molecular classifications, KRAS represents about 30% of all lung adenocarcinomas. Our group has recently investigated if co-mutations within KRAS-mutated lung tumors can aid in identifying a unique therapeutic strategy for patient treatment. Given that tumors exert a strong influence over the immune system and the recent successes in immune targeting via checkpoint blockade therapy in various cancers, including lung, we hypothesized that co-mutational subgroups of KRAS-mutant NSCLC elicit distinct immune profiles and support a rationale for evaluating these subgroups in conjunction with appropriate immunotherapies for further clinical testing. To investigate this phenomenon, we performed a supervised analysis of 86 immune-related genes from The Cancer Genome Atlas data set in lung adenocarcinomas with KRAS mutations and TP53 or STK11(LKB1) co-mutations. The results from our analysis revealed that KRAS-mutant NSCLC with LKB1 (KL) and TP53 (KP) co-mutations have distinct immune profiles. KP tumors have an increase in (1) PD-L1 and PD-L2; (2) co-stimulation via CD40, CD80, CD86; (3) antigen presentation HLA-I, HLA-II, and CD1; (4) FOXP3 and CD4, indicating T regulatory populations; (5) CD33, CD11b, and CD11c, which are potentially suppressive myeloid cell populations. We conclude that KRAS co-mutations can create significantly different immune microenvironments; KRAS + TP53 (KP) mutant tumors may specifically benefit from checkpoint blockade, depletion of immunosuppressive myeloid and T regulatory populations, but could support de novo anti-tumor T cell expansion due to high expression of co-stimulatory molecules and HLA-I and HLA-II expression. Conversely, KRAS + LKB1 (KL) mutant tumors have an immunosuppressed or inert phenotype and may potentially benefit from adoptive cell transfer of anti-tumor T cells in conjunction with or in lieu of checkpoint blockade. Citation Format: Warren L. Denning, Lixia Diao, Ferdinandos Skoulidis, Yanyan Lou, Lauren Byers, Jing Wang, John Weinstein, Don Gibbons, John Heymach. Defined co-mutation subgroups of KRAS-mutated NSCLC display distinct immune profiles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 456. doi:10.1158/1538-7445.AM2015-456