Lung-tropic, liver-averse, primary PDAC tumors are associated with greater peripheral T cell diversity and have a unique, subtype-independent, gene-expression signature that significantly correlates with longer survival.

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related death in the United States, and most patients who present with metastatic PDAC die within a year. However, we and others have found that patients with lung metastases in the absence of liver metastases survive significantly longer than patients who present with liver metastases. We analyzed an unpublished RNASeq dataset from ~300 tumor-enriched samples from primary and metastatic PDAC specimens. Consistent with many previous publications, we found that patients with basal/squamoid-subtype tumors had significantly worse outcomes than patients with classical/ductal-subtype tumors. Additionally, we identified that most primary tumors from patients who develop lung – but not liver – metastases are classical subtype. However, this association did not wholly account for the pro-survival effect of lung-tropic, liver-averse metastatic disease because patients with lung-tropic, liver-averse, classical-subtype, primary tumors had significantly better outcomes than patients with liver-tropic, classical-subtype tumors. To identify and parse metastatic organotropism from subtype, we used organotropism-independent and subtype-independent, primary-tumor training cohorts to generate two non-overlapping gene sets that were significantly enriched in test cohorts of either primary, basal-subtype or liver-tropic tumors over primary tumors that were classical-subtype or lung-tropic and liver-averse, respectively. When applied to all primary tumors in our dataset, both the subtype-specific and organotropism-specific gene sets significantly correlated with patient outcome. From an unpublished analysis of TCRbeta CDR3 sequences from ~250 paired blood and primary tumor samples, we identified significantly greater TCRbeta diversity in blood and primary tumors from patients with lung-tropic, liver-averse disease. Additionally, we found evidence that TCRbeta rearrangements from liver-tropic primary tumors were more likely to be found in autologous peripheral blood samples than TCRbeta rearrangements from lung-tropic, liver-averse primary tumors. We also found that TCRbeta sequences were often shared between samples from patients with liver-tropic disease but never shared between samples from patients with lung-tropic, liver-averse disease. Overall, our results point to a lung-tropic, liver-averse form of PDAC that – independent of tumor subtype – leads to positive outcomes, and that T cell diversity may have a causal relationship and/or may serve as a biomarker of long-term survival with lung-tropic, liver-averse disease. Citation Format: Jason M. Link, Patrick J. Worth, Dove Keith, Sydney Owen, Alison Grossblatt-Wait, Carl Pelz, Hannah Holly, Motoyuki Tsuda, Kevin MacPherson, Jonathan Brody, Charles Lopez, Brett C. Sheppard, Rosalie C. Sears. Lung-tropic, liver-averse, primary PDAC tumors are associated with greater peripheral T cell diversity and have a unique, subtype-independent, gene-expression signature that significantly correlates with longer survival [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-007.