T-cell receptor repertoire analysis reveals positive correlation between intra-tumoral clonotype diversity and overall survival in patients with pancreatic ductal adenocarcinoma

Abstract

Presenter: Vikram Pothuri BA | Washington University, St. Louis Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune therapy. Nevertheless, it is well established that intra-tumoral T-cell infiltration correlates with improved overall survival (OS). This highlights the importance of characterizing the global T-cell receptor (TCR) repertoire. We hypothesized that a more clonal TCR repertoire, suggestive of a primed tumor-specific T-cell response, would correlate with increased survival. Methods: Our study included 162 patients diagnosed with PDAC that underwent surgical resection between 2011-2019. Matched peripheral blood mononuclear cells (PBMC) and tumor tissue were banked from 123 patients and PBMC alone from 39 patients. TCR CDR3 regions were sequenced, enabling identification and quantification of both intra-tumoral and circulating T-cell clonotypes. We analyzed two metrics of TCR repertoire diversity: richness (number of unique clonotypes) and evenness (distribution of clonotypes). Results: In 114 matched samples, TCR repertoires in PBMC were significantly more diverse (Wilcoxon p < 0.003) than in tumor. When controlling for age, stage (I vs. II vs. III), neoadjuvant treatment (none vs. chemotherapy vs. chemotherapy plus radiation), and diversity in PBMC, fraction T-cells of nucleated cells positively correlated with increased OS (Multivariate Cox, HR (95% CI) = 0.05 (0.01-0.49), p = 0.01). When controlling for age, stage (I vs. II vs. III), neoadjuvant treatment (none vs. chemotherapy vs. chemotherapy plus radiation), and fraction T-cells in tissue, diversity in the upper quartile of the cohort is associated with increased OS compared to diversity in the lower three quartiles of the cohort (Multivariate Cox, HR (95% CI) = 0.42 (0.22-0.82), p = 0.01). Conclusion: Frequency of circulating T-cells, but not circulating TCR diversity, positively correlated with OS. Contrastingly, in tumors, TCR repertoire diversity, but not T-cell frequency, significantly correlated with OS. The intra-tumoral data indicates that a broader repertoire of TCRs within the tumor may offer a survival advantage. This offers insight into responses of PDAC to immunotherapy and emphasizes the importance of evaluating the tissue specific TCR repertoire, which may offer insights into patient outcome.