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Tumor Neoantigen Burden and Immune Environment in Driver Alteration-Positive Lung Adenocarcinoma

World Conference on Lung Cancer 2020 Presentation
Authors Benjamin Leibowitz, Lara Kujtan, Leo Shunyakov, Anna E. Schwarzbach, Apar K. Ganti, Ashiq Masood, and Janakiraman Subramanian


Immune checkpoint inhibitors (ICI) provide limited benefit in patients with EGFR-ALK- or ROS1-positive lung adenocarcinoma (LUAD), while patients with BRAF- and KRAS-positive LUAD demonstrate better responses. To understand the differential response to ICI in driver gene-altered LUAD, we performed a comparative analysis of their tumor neoepitope load and immune environment.


De-identified molecular data from 2,740 LUAD patients previously sequenced with Tempus|xT, a 648-gene DNA panel (Tempus Labs, Chicago, IL) were analyzed. Whole-exome capture RNAseq was performed on 1,454 of these samples. Driver mutational status was correlated with neoepitope load and immune infiltration enrichment. Neoantigen prediction was performed on all non-silent mutations using tumor only or tumor/normal matched samples, and immune infiltration scores were predicted using a machine-learning model trained on mRNA expression and pathologist-scored IHC data (PMID:31570899). Distributions of predicted neoantigens and immune infiltration, including CD8+/CD4+ T-cells, B-cells, NK cells, and macrophages, between driver-gene altered LUAD (defined as patients with alterations in KRASEGFRALKBRAFMETPIK3CAROS1RET, or ERBB2) and driver-gene wild type (WT) LUAD were compared using two-sided Wilcoxon tests.


Non-synonymous antigenic mutations were predicted for all DNA-sequenced tumors. The median neoepitope load was 13 (range 1-406) and WT tumors had the highest median neoepitope load (Table). EGFR-MET-RET-ALK-ROS1– and BRAF-positive tumors had significantly lower neoepitope load than WT, with BRAF-positive LUAD having the highest neoepitope load in this group (Table). Neoepitope loads of KRAS-, ERBB2- and PIK3CA-positive tumors were not significantly different from WT. PD-L1 status was not associated with neoantigen load after controlling for driver mutation status. Overall immune infiltration was higher in MET– and BRAF-positive LUAD compared to WT (Table). Relative to WT, KRAS– and PIK3CA-positive tumors had higher CD4+ T-cell infiltration, while EGFR-positive had significantly lower CD8+ T-cell infiltration (P<0.001, P=0.03 and P<0.0001, respectively).


The high neoepitope load and unique immune composition in KRAS- and BRAF-positive LUAD may be associated with better response to ICI typically observed in these tumors. High immune infiltration in MET-positive LUAD suggests that ICI may be more beneficial in these tumors. Cumulatively, our findings suggest that the significant variability in neoepitope load and immune environment of driver-gene altered LUAD might explain their differential sensitivity to ICI. Ongoing studies are evaluating the impact of neoepitope load on clinical characteristics and outcomes.