Introduction: It is currently unknown how specific mutational processes that sculpt the genome of non-small-cell lung cancer (NSCLC) impact the tumor immune micro-environment. APOBEC-mediated cytidine deamination has emerged as a major source of somatic mutation across several epithelial malignancies, including NSCLC. Among the 11 APOBEC family members, APOBEC3B (A3B) is overexpressed in several cancers and has been considered the dominant mutator deaminase. However, recent data have also implicated APOBEC3A (A3A) as an important contributor to tumor somatic hypermutation. In this study, we evaluated the relationship(s) between A3B/A3A expression and the immune contexture of LUAC.
Methods: Our datasets include two large cohorts of chemotherapy-naïve, early stage LUAC: a) the TCGA collection of 431 LUACs with available RNASeq data and b) the PROSPECT dataset of 183 LUACs with available array-based mRNA expression data (Illumina platform) and automated IF-based quantitative analysis of immune cell sub-populations for 107 tumors included in a tissue micro-array (TMA). We have further extended our studies to include two datasets of metastatic, platinum-refractory LUACs from the BATTLE-1 and BATTLE-2 clinical trials of targeted therapy. Finally, we have analyzed an in-house panel of 78 comprehensively annotated NSCLC cell lines.
Results: Expression of A3B correlated significantly with the expression of CD274 (PD-L1) in both the TCGA (r = 0.25, P = 1.49e−07) and PROSPECT (r = 0.168, P = 0.023) cohorts, as well as in our panel of NSCLC cell lines (r = 0.283, P = 0.012). The correlation was stronger among KRAS-mutant LUACs (r = 0.462, P = 7.64e−08, TCGA). Within co-mutation defined subgroups of KRAS-mutant LUAC, KP (KRAS;TP53) tumors expressed significantly higher levels of A3B mRNA (P = 4.41e−08, ANOVA). When data were dichotomized into top and bottom tertiles for A3B mRNA expression, A3B-high tumors expressed significantly higher levels of CD274 mRNA in both the TCGA (P = 3.32e−08, t-test) and PROSPECT (P = 0.0096, t-test) cohorts. Importantly, A3B-high tumors displayed increased density of intra-tumoral CD8+ T-lymphocytes (P = 0.03, Mann-Whitney test). Analysis of chemo-refractory tumors from the BATTLE trials and assessment of the impact of the A3B deletion polymorphism are underway and updated results will be presented at the meeting.
Conclusions: Elevated expression of A3B is associated with a “hot” tumor immune micro-environment with engagement of PD-1/PD-L1 axis immune checkpoints. Distinct mutagenic processes may shape the tumor immune microenvironment and present opportunities for targeted intervention with immunotherapy.
Citation Format: Edwin R. Parra, Pan Tong, Humam Kadara, Vassiliki Papadimitrakopoulou, Julie Izzo, Jaime Rodriguez-Canales, Carmen Behrens, John D. Minna, Jing Wang, Ignacio I. Wistuba, John V. Heymach, Ferdinandos Skoulidis. Impact of APOBEC mutagenesis on the immune microenvironment of lung adenocarcinoma (LUAC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 532.