Abstract A082: Distinct subsets of cytotoxic CD8 T cells delineate the rare pancreatic tumors that respond to PD-1 blockade
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Abstract A082: Distinct subsets of cytotoxic CD8 T cells delineate the rare pancreatic tumors that respond to PD-1 blockade
- Date Crossref
- 28/09/2025
- Éditeur
- American Association for Cancer Research (AACR)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Dana-Farber Cancer Institute pays non établi dans la noticeStructure de recherche
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Caris Life Sciences (United States) pays non établi dans la noticeEntreprise
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Massachusetts General Hospital pays non établi dans la noticeÉtablissement de santé
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Virginia Commonwealth University pays non établi dans la noticeUniversité ou école supérieure
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Massachusetts Institute of Technology pays non établi dans la noticeUniversité ou école supérieure
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Brigham and Women's Hospital pays non établi dans la noticeÉtablissement de santé
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Dana-Farber Brigham Cancer Center pays non établi dans la noticeÉtablissement de santé
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Boston pays non établi dans la noticeInstitution
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Irving pays non établi dans la noticeInstitution
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Richmond pays non établi dans la noticeInstitution
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Cambridge pays non établi dans la noticeInstitution
Dana-Farber Cancer Institute, Caris Life Sciences (United States) et Massachusetts General Hospital, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.