Abstract A082: Distinct subsets of cytotoxic CD8 T cells delineate the rare pancreatic tumors that respond to PD-1 blockade

Abstract Inhibitors of the immune checkpoint PD-1 (ɑPD1) have had spectacular success in otherwise highly lethal malignancies, such as metastatic melanoma, but are ineffective in pancreatic ductal adenocarcinoma (PDAC), despite evidence of tumor infiltration by PD1+ T cells. A rare subset of PDAC patients with mismatch repair deficiency (MMRd) and/or high tumor mutational burden (TMB-H) offer an intriguing opportunity to understand effective T cell responses in pancreatic cancer. In this work, we performed whole-exome and bulk RNA sequencing analyses of 7,950 pancreatic tumors. We found that the MMRd tumors were distinguished by a signature of CD8 T cell infiltration and interferon-γ signaling. We then performed single-cell RNA-seq and TCR-seq of select tumors from TMB-H and TMB-L patients treated with or without PD-1 blockade. Clinical response to PD1 blockade in TMB-H tumors was associated with a remarkable CX3CR1+ CD8 T cell response, with prominent expansion of these cells in both the tumor and in circulation. In TMB-low tumors, we instead observed CXCL13+ and HOBIT+ tissue-resident CD8 cell subsets that were unable to mount a tumor-rejecting response, despite reinvigoration with ɑPD1 as evidenced by clonotypes actively entering into cell cycle. Reasoning that the key distinction between a TMB-H and TMB-L pancreatic tumor is the antigen repertoire, we hypothesize that the quality of the antigens present in the tumor is the pivotal factor in determining responsiveness to PD1 blockade in pancreatic cancer. Citation Format: Lestat Ali, Kieran Sweeney, Chong Zuo, Patrick Lenehan, Eugena Chang, S. Jennifer Wang, Casey Brackett, Joshua Remland, Lauren Brais, William Lopes, Thomas Clancy, James Cleary, Jason Hornick, Brandon Huffman, George Molina, Mark Fairweather, Jonathan Nowak, Kimberly Perez, Douglas Rubinson, Benjamin Schlecter, Sarah Slater, Ritchell van Dams, Jiping Wang, Lei Zhao, Brian Wolpin, Stephanie Dougan, Harshabad Singh. Distinct subsets of cytotoxic CD8 T cells delineate the rare pancreatic tumors that respond to PD-1 blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A082.