Immune Landscape Of Endometrial Carcinoma And Its Association With Neoantigen Landscape And Tgf-Beta Signaling Pathway Related Genes Mutation Status.

Abstract We aimed to understand how TGF-β signaling pathway related gene mutation affects the tumor neoantigen burden and immune landscape in uterine corpus endometrial carcinoma (UCEC). cBioPortal was queried to obtain the UCEC The Cancer Genome Atlas (TCGA) cohort data (521 patients). TGF-β signaling pathway related gene mutation was defined as genetic variances in TGFBR1, TGFBR2, ACVR2A, ACVR1B, SMAD2, SMAD3, or SMAD4. The neoantigen counts were predicted using CloudNeo pipeline. CIBERSORT was used to predict tumor-infiltrating immune cells. In 521 UCEC patients, 124 had mutations in TGF-β signaling pathway related genes. These tumors with the mutations had significantly higher neoantigen counts, mutation counts, and cytolytic scores (a geometric mean of mRNA expression of perforin and granzyme), and a trend towards higher PD-L1 expression level (Table 1). When subdivided by molecular subtypes, similar patterns were seen in most groups. TGF-β signaling pathway gene mutation was significantly associated with tumor tissue infiltration by CD8 T cells (18.3% vs 10.5%; p< 0.05), active CD4 memory T cells(13.0% vs 7.5%; p<0.001), follicular helper T cells (11.0% vs 7.5%; p<0.001), M1 macrophage(5.8% vs 3.9%; <0.001) and M2 macrophage(12.6% vs 9.8%; p<0.05), but negatively associated with infiltration by plasma cells(2.6% vs 4.4%; p<0.05), naïve CD4T cells (2.3% vs 3.3%; p< 0.05), resting CD4 memory T cells(10.6% vs 15.1%; p<0.001), and Tregs (4.4% vs 5.7%; p<0.05). We first report that the TGF-β-signaling pathway-related gene mutation is significantly correlated with neoantigen burdens, mutations counts, and cytolytic activities in UCEC tissues. Consistently, the mutation was associated with tumor infiltration by CD8T and active CD4 T cells, but negatively associated with infiltration by Tregs. Further studies are warranted to explore the utility of TGF-β pathway mutations as potential favorable biomarkers with immunotherapy in UCEC. Immune landscape of endometrial carcinoma according to TGF-β pathway related gene mutationnumber of valuesneoantigenmutation countcytolytic scorePD-L1 expressionAll521166.1964.5189.914.1TGF-β pathway related gene nonmutated39652.3219.415813.4TGF-β pathway related gene mutated124528.4**3350.0**293.2*16.3POLEmutAll85741.04925268.619.0nonmutated28158.9941.6183.517.7mutated571027.0**6881.0**310.4*19.6MSI-HAll167297.51455.0251.814.8nonmutated99157.1539.5207.714.7mutated68501.9**2787.0**315.915.0P53abnAll192134.7904.1202.616.8nonmutated14820.390.8142.215.6mutated44519.3**3640.0**407.218.5NSMPAll16111.5254.9131.59.7nonmutated15411.554.6133.39.6mutated712.960.491.612.1Values are expressed as mean.*p<0.05,**p<0.0001.MSI-H, microsatellite instability-high; NSMP, no specific molecular profile Citation Format: William H. Bae, Jin Young Hwang, Won Kyung Hur, Myungwoo Nam, Yoonhee Choi, Leeseul Kim, Yeun Ho Lee, William Cheng, Eugene Kim, Emma Yu, Chan Mi Jung, Heayoon S. Cho, Jeff Chuang, Victor Wang, Young Kwang Chae. Immune landscape of endometrial carcinoma and its association with neoantigen landscape and TGF-β signaling pathway related genes mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 451.