Distinct T cell receptor diversity and integrative analyses of clinically defined high-grade serous ovarian cancer

Abstract

<h3>Objectives:</h3> To characterize distinct T cell repertoires between clinically well-defined groups of high-grade serous ovarian cancer (HGSC) patients, we obtained pre- treatment tumor samples via a laparoscopic triage algorithm. <h3>Methods:</h3> Pre-treated frozen tumor samples (one primary and two metastatic sites) were collected from patients with HGSC based on a laparoscopic triage algorithm: 1) patients who underwent complete gross resection after primary surgery (R0, n=10), 2) patients who received neoadjuvant chemotherapy (NACT) with excellent response (NACT-ER, n=10), or 3) patients who received NACT with poor response (NACT-PR, n=10). These samples were subjected to high-throughput TCR sequencing analysis and integrative analyses, with immune assessments and high-depth whole-genome sequencing from the matched samples among the groups. <h3>Results:</h3> We identified a rearranged complementary-determining region 3 (CDR3) of the T-cell receptor β (TCRβ) gene using a total of 90 samples. Importantly, we identified higher TCR β-chain CDR3 diversity (i.e., a higher number of unique productive sequences, less clonal relatedness, and higher TCR convergence) in the R0 group than in the NACT groups. We also found enrichment of specific variable (V), diversity (D), and joining (J) genes usage in each group and significant unique mutual exclusivity and co-occurrence of V, D, and J genes in all three groups. In addition, we also found significant positive correlations between clonal relatedness and neoantigens (R=0.31, p=0.007), copy number variations (R=0.43, p<0.001), and mutation load (R=0.27, p=0.019) by integrative analyses. We also observed significant negative correlations between TCR clonal relatedness and the percentage of T cells (CD8+ and CD4+, <0.001) and B cells (CD20+) from immune profiling data. <h3>Conclusions:</h3> Our findings provide a comprehensive understanding of TCR repertoire diversity in clinically defined HGSC subgroups, and could have prognostic and therapeutic strategies in HGSC.