However, there is an urgent need for predictive biomarkers to determine who will likely benefit most from which therapy. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may facilitate rational application of immunotherapies.Ĭorrespondence: Priyanka Subrahmanyam checkpoint blockade has greatly improved clinical outcomes in melanoma patients. Our results identify neoantigens with unique qualities as T cell targets in PDAC. Finally, we detected lasting circulating T cell reactivity to both high quality neoantigens and cross-reactive antigens in PDAC survivors, including identical intratumoral clones with specificity to both (n=5 of 7 patients tested). Similarly, neoantigen quality, but not quantity, was independently prognostic of survival in a larger, independent cohort unselected by survival (n =166 Neoantigen Quality Hi vs. 0.8y P=0.002) whereas a model ascribing greater immunogenicity to increasing neoantigen number did not (Neoantigen Quantity Hi vs. In investigating possible unique neoantigen qualities in long-term survivors, a neoantigen quality model conferring greater immunogenicity to dominant neoantigens with homology to microbial epitopes identified long-term survivors independent of confounding variables and chemotherapy (Neoantigen Quality Hi vs.

In examining neoantigens as potential T cell targets, we found that patients with both the highest predicted neoantigen number and the greatest CD3 +CD8 + infiltrates together but not either parameter alone, exhibited the longest survival (median OS not reached vs. Tumors of long-term survivors exhibited greater TCR repertoire diversity compared to tumors of short-term survivors, implying differential antigenic targets. We found that tumors of long-term survivors displayed 12-fold greater cytolytic CD3 +CD8 +Granzyme-B + cells, with >94% of intratumoral T cell clones unique to tumors and not shared with adjacent normal pancreatic tissue, suggesting intratumoral antigen recognition. To examine in vivo T cell-neoantigen reactivity, we used functional assays in a subset of very long-term PDAC survivors (n=7, median OS 10.5 years). To assess differential neoantigen immunogenicity, we performed neoantigen fitness modeling integrating clonal genealogy, epitope homology, and T cell receptor affinity.

To enable antigen discovery, we performed a combined analysis of whole exome sequencing, neoantigen prediction, T cell receptor (TCR) Vβ-chain sequencing, 9-color multiplexed immunohistochemistry, and tumor transcriptomic profiling. To identify T cell antigens in long-term PDAC survivors, we assembled the largest cohorts of stage-matched short and long-term PDAC survivors (n=82, median OS 6y).

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