Abstract 5935: Higher tumor mutation burden (TMB) is associated with the presence of DNA repair gene mutations, T-cell infiltration, and favorable survival outcome in ovarian carcinoma
Authors: Chae Young Kwang , Bae William H. , Murshudova Sabina , Anker Jonathan F. , Kim Young Suk , Pineda Mario J. , Nieves-Neira Wilberto , Matei Daniela , Lurain John R. , Shahabi Shohreh , Giles Francis J. 
Published: July 2017

Immunotherapy is being explored as a promising therapeutic option in ovarian cancer. However, little progress has been made in our understanding of the immune cell landscape in the tumor microenvironment and its association with genomic features in ovarian cancer.

The RNA-seq values of immune “metagene” markers that are specific to each of 28 cell types (Angelova et al. 2015) from the TCGA database were analyzed to determine the tumor infiltration by immune cells in 307 patient samples (185 sequenced) with ovarian carcinoma.

Tumor tissues were most frequently infiltrated by all T cells (46.91%), activated CD4 T(19.87%) and activated CD8 T(16.94%) cells. Activated CD8 T cells were significantly co-infiltrated by NK56 bright, effector memory CD4 T, activated CD4 T, myeloid dendritic cell (DC) and plasmacytoid DC. The tumors with mutated homologous recombination (HR) genes, including ATR, ATM, CHEK1, CHEK2, BRCA1, BRCA2, BAP1, BARD1, FANCD2, FANCE, FANCC, FANCA, RAD50, RAD51, and PALB2, demonstrated a significant 1.36-fold increase in average mutation counts compared to the wild-types (p &lt; 0.01). Mutations in mismatch repair genes had no statistically significant association with the average mutation counts. Tumors with high mutation counts showed a significantly increased infiltration by activated CD8 T cells and immature DCs (Table1, p &lt; 0.05). The highest quartile in tumor mutation burden (TMB) was associated with a significant 16.7 months longer overall survival (OS) compared to the lowest quartile (p &lt; 0.01).

Our study demonstrated that higher TMB is associated with the presence of DNA repair gene mutations, activated CD8 T cell infiltration, and favorable survival outcome in ovarian carcinoma.

Fold change in the percent of patients with infiltration by each immune cellHigh TMBLow TMBFold change†p-value††Immune cell subtypes*Percent of patients with infiltration (%)Percent of patients without infiltration (%)Percent of patients with infiltration (%)Percent of patients without infiltration (%)iDC3.2447.570.0049.19NA0.01Th172.1648.650.5448.654.000.19Immature B cells3.2447.571.0848.113.030.16Mast cells2.7048.111.0848.112.500.27Macrophages3.7847.031.6247.572.360.21Activated CD811.8938.925.4143.782.480.03Effector Memory CD45.4145.412.7046.492.050.20mDC3.7847.032.1647.031.750.38Activated B cells4.3246.493.2445.951.320.62All B cells5.4145.414.3244.861.240.67All immune cells31.3519.4627.5721.621.260.43All T cells23.7827.0323.7825.410.940.83NK56 dim2.1648.652.1647.030.970.96Activated CD48.1142.709.1940.000.830.62Th13.7847.034.3244.860.830.74Treg1.0849.731.6247.570.640.62NKT1.6249.192.7046.490.570.44Central Memory CD81.0849.732.7046.490.370.23*Excluded cell types with &lt;5 tumor infiltrations. iDC, immature dentric cells; mDC, myeloid dendritic cells; NKT, NK T cells; Treg, regulatory T cells. †Fold change = Proportion of tumors infiltrated by immune cells among high TMB tumors / Proportion of tumors infiltrated by immune cells among low TMB tumors. ††Chi-squared test

Citation Format: Young Kwang Chae, William H. Bae, Sabina Murshudova, Jonathan F. Anker, Young Suk Kim, Mario J. Pineda, Wilberto Nieves-Neira, Daniela Matei, John R. Lurain, Shohreh Shahabi, Francis J. Giles. Higher tumor mutation burden (TMB) is associated with the presence of DNA repair gene mutations, T-cell infiltration, and favorable survival outcome in ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5935. doi:10.1158/1538-7445.AM2017-5935