---
title: "Neoantigen-reactive CD8+ T cell engagement defines exceptional pancreatic cancer survivors"
id: "biorxiv-23-neoantigen-reactive-cd8-t-cell-engagement-marks-exceptional-survivors-of"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-23-neoantigen-reactive-cd8-t-cell-engagement-marks-exceptional-survivors-of"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.17.752426v1?rss=1"
published_at: "2026-09-18T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Neoantigen-reactive CD8+ T cell engagement defines exceptional pancreatic cancer survivors
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-23-neoantigen-reactive-cd8-t-cell-engagement-marks-exceptional-survivors-of
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.17.752426v1?rss=1)
- **Published At:** 2026-09-18T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Pancreatic cancer is generally resistant to **immune checkpoint blockade (ICB)**, though tumors with homologous recombination deficiency (HRD) may benefit. - In the POLAR trial, patients received maintenance **pembrolizumab** plus **olaparib** after platinum-based chemotherapy; clinical responses were variable. - The investigators combined longitudinal blood TCR sequencing with tumor single-cell and spatial profiling to identify determinants of productive antitumor immunity. - Durable clinical benefit correlated with rare tumor-infiltrating, peripherally expanding (TIE) **CD8+ T cell** clonotypes; some of these clonotypes were functionally **neoantigen-reactive**. - Patients positive for the TIE signature (TIE⁺) exhibited substantially prolonged survival that exceeded predictions from established genomic and immune biomarkers. - Resistance-associated features included spatial exclusion of T cells, stromal remodeling rich in myofibroblastic cancer-associated fibroblasts (myCAF), malignant-cell programs linked to basal-like state and KRAS, and expansion of **CTLA4+ regulatory T cells** tied to local immunosuppressive remodeling. - The study proposes a clonotype-resolved framework for immune monitoring and highlights complementary stromal, tumor-intrinsic, and regulatory immune barriers that may inform rational combination immunotherapy strategies in pancreatic cancer. - Details such as sample sizes, specific survival metrics, and experimental parameters were not reported in the provided source text.
## Clinical Analysis & Structured Key Points
Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer | bioRxiv Skip to main content New Results Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer View ORCID Profile Marc Hilmi , Joshua D. Schoenfeld , Wilson McKerrow , Yuval Elhanati , Catherine A. O'Connor , Shigeaki Umeda , Nicolas Lecomte , Jerry P. Melchor , Agustin Cardenas III , Maria Lao , Vincenzo Nasca , Elias-Ramzey Karnoub , Nuray Tezcan , Zeynep Tarcan , Joanne F. Chou , Roshan Sharma , Junmin Song , Michael May , Fiyinfolu Balogun , Kenneth H. Yu , Kevin Soares , Charlotte Reiche , Martina Milighetti , Dana Pe'er , Santosha A. Vardhana , Marinela Capanu , Olca Basturk , Benoit Rousseau , Yohyoh Wang , Jayon Lihm , Neeman Mohibullah , Vineet Rolston , Ernesto Santos , Marsha Reyngold , Alice Wei , Vinod Balachandran , Mara H. Sherman , Nadeem Riaz , Christine Iacobuzio-Donahue , Benjamin Greenbaum , Eileen M. O'Reilly , Wungki Park doi: https://doi.org/10.64898/2026.09.17.752426 Marc Hilmi 1 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Institut Curie, Paris, France.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Marc Hilmi Joshua D. Schoenfeld 2 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Wilson McKerrow 3 The Halvorsen Center for Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yuval Elhanati 3 The Halvorsen Center for Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Catherine A. O'Connor 4 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Harvard Medical School, Boston, MA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shigeaki Umeda 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nicolas Lecomte 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jerry P. Melchor 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Agustin Cardenas III 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maria Lao 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vincenzo Nasca 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elias-Ramzey Karnoub 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nuray Tezcan 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Zeynep Tarcan 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joanne F. Chou 7 Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roshan Sharma 8 Single-cell Analytics Innovation Lab, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Junmin Song 5 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael May 2 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fiyinfolu Balogun 2 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kenneth H. Yu 2 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kevin Soares 9 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Departm; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Charlotte Reiche 10 The Halvorsen Center for Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New Yo; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Martina Milighetti 10 The Halvorsen Center for Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New Yo; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dana Pe'er 11 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Santosha A. Vardhana 12 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marinela Capanu 13 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Olca Basturk 14 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Benoit Rousseau 15 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yohyoh Wang 16 Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jayon Lihm 16 Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Neeman Mohibullah 17 Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vineet Rolston 2 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ernesto Santos 18 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marsha Reyngold 19 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alice Wei 20 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vinod Balachandran 21 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mara H. Sherman 22 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nadeem Riaz 19 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christine Iacobuzio-Donahue 23 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Benjamin Greenbaum 24 The Halvorsen Center for Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eileen M. O'Reilly 2 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Wungki Park 25 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Divi Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: parkw1{at}mskcc.org Abstract Info/History Metrics Supplementary material Preview PDF Abstract Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB), although homologous recombination-deficient (HRD) tumors may derive benefit. In the POLAR trial of maintenance pembrolizumab plus olaparib after platinum-based chemotherapy for metastatic PC, responses remained heterogeneous. To define determinants of productive antitumor immunity, we integrated longitudinal blood TCR sequencing with tumor single-cell and spatial profiling. Durable benefit was associated with rare tumor-infiltrating, peripherally expanding (TIE) CD8+ T cell clonotypes, a subset of which were functionally neoantigen-reactive. TIE⁺ patients showed markedly prolonged survival beyond established genomic and immune biomarkers. Conversely, resistance was associated with spatial T cell exclusion, myCAF-rich stromal remodeling, basal-like/KRAS-associated malignant-cell programs, and expansion of CTLA4⁺ regulatory T cells linked to local immunosuppressive remodeling. These findings define a clonotype-resolved framework for immune monitoring and identify complementary stromal, tumor-intrinsic, and regulatory immune barriers that may guide rational combination immunotherapy in PC. Competing Interest Statement M.H. reports honoraria from Pierre Fabre, AstraZeneca, Amgen, and Viatris; research funding from Servier; and travel support from Astellas. J.D.S. reports prior consulting for Hoplite Healthcare and serves on the medical advisory board of OpenEvidence, both unrelated to this work. M.M. is an inventor on a patent application related to identifying clones by unique trajectories. K.H.Y. reports a relationship with Ipsen Pharma. D.P. serves on the scientific advisory board of insitro. S.A.V. reports prior consulting for Generate Biomedicines and research funding from Bristol Meyers Squibb unrelated to this work. V.B. reports relationships with Genentech, Merck, and AbbVie. N.R. reports research funding from Pfizer. E.M.O. reports institutional research funding from Arcus, Genentech/Roche, BioNTech, Incyte, AstraZeneca, Elicio Therapeutics, Digestive Care, Agenus, Amgen, Revolution Medicines, and Tango Therapeutics; uncompensated consulting or DSMB activities for Arcus, Actithera, Amgen, Astellas, AstraZeneca, Corcept, Pfizer, Agenus, BioNTech, Ipsen, Ikena, Merck, Immuneering, Moma Therapeutics, Novartis, BMS, Revolution Medicines, Regeneron, Systimmune, Silexion, Tango Therapeutics, and Verastem; travel support from BioNTech, Pfizer, and Revolution Medicines; and other relationships with AACR, ASCO, Imedex, Research To Practice, NIH/NCI, Break Through Cancer, TouchIme, PeerView Voice, and PeerView. W.P. reports institutional research funding from Break Through Cancer, Parker Institute for Cancer Immunotherapy, The Society of MSK, Merck, Astellas, Lepu Biopharma, Amgen, and Revolution Medicines, and consulting for Astellas, EXACT Therapeutics, Revolution Medicines, and Innovent Bio. All other authors declare no competing interests. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 18, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer Marc Hilmi , Joshua D. Schoenfeld , Wilson McKerrow , Yuval Elhanati , Catherine A. O'Connor , Shigeaki Umeda , Nicolas Lecomte , Jerry P. Melchor , Agustin Cardenas III , Maria Lao , Vincenzo Nasca , Elias-Ramzey Karnoub , Nuray Tezcan , Zeynep Tarcan , Joanne F. Chou , Roshan Sharma , Junmin Song , Michael May , Fiyinfolu Balogun , Kenneth H. Yu , Kevin Soares , Charlotte Reiche , Martina Milighetti , Dana Pe'er , Santosha A. Vardhana , Marinela Capanu , Olca Basturk , Benoit Rousseau , Yohyoh Wang , Jayon Lihm , Neeman Mohibullah , Vineet Rolston , Ernesto Santos , Marsha Reyngold , Alice Wei , Vinod Balachandran , Mara H. Sherman , Nadeem Riaz , Christine Iacobuzio-Donahue , Benjamin Greenbaum , Eileen M. O'Reilly , Wungki Park bioRxiv 2026.09.17.752426; doi: https://doi.org/10.64898/2026.09.17.752426 Share This Article: Copy Citation Tools Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer Marc Hilmi , Joshua D. Schoenfeld , Wilson McKerrow , Yuval Elhanati , Catherine A. O'Connor , Shigeaki Umeda , Nicolas Lecomte , Jerry P. Melchor , Agustin Cardenas III , Maria Lao , Vincenzo Nasca , Elias-Ramzey Karnoub , Nuray Tezcan , Zeynep Tarcan , Joanne F. Chou , Roshan Sharma , Junmin Song , Michael May , Fiyinfolu Balogun , Kenneth H. Yu , Kevin Soares , Charlotte Reiche , Martina Milighetti , Dana Pe'er , Santosha A. Vardhana , Marinela Capanu , Olca Basturk , Benoit Rousseau , Yohyoh Wang , Jayon Lihm , Neeman Mohibullah , Vineet Rolston , Ernesto Santos , Marsha Reyngold , Alice Wei , Vinod Balachandran , Mara H. Sherman , Nadeem Riaz , Christine Iacobuzio-Donahue , Benjamin Greenbaum , Eileen M. 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