Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer
- 1David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Ket
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.
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BibTeX
@misc{hilmi2026neoantigenreactive,
title = {{Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer}},
author = {M. Hilmi and J. D. Schoenfeld and W. McKerrow and Y. Elhanati and C. A. O'Connor and S. Umeda and N. Lecomte and J. P. Melchor and A. Cardenas and M. Lao and V. Nasca and E.-R. Karnoub and N. Tezcan and Z. Tarcan and J. F. Chou and R. Sharma and J. Song and M. May and F. Balogun and K. H. Yu and K. Soares and C. Reiche and M. Milighetti and D. Pe'er and S. A. Vardhana and M. Capanu and O. Basturk and B. Rousseau and Y. Wang and J. Lihm and N. Mohibullah and V. Rolston and E. Santos and M. Reyngold and A. Wei and V. Balachandran and M. H. Sherman and N. Riaz and C. Iacobuzio-Donahue and B. Greenbaum and E. M. O'Reilly and W. Park},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752426},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752426v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer
AU - M. Hilmi
AU - J. D. Schoenfeld
AU - W. McKerrow
AU - Y. Elhanati
AU - C. A. O'Connor
AU - S. Umeda
AU - N. Lecomte
AU - J. P. Melchor
AU - A. Cardenas
AU - M. Lao
AU - V. Nasca
AU - E.-R. Karnoub
AU - N. Tezcan
AU - Z. Tarcan
AU - J. F. Chou
AU - R. Sharma
AU - J. Song
AU - M. May
AU - F. Balogun
AU - K. H. Yu
AU - K. Soares
AU - C. Reiche
AU - M. Milighetti
AU - D. Pe'er
AU - S. A. Vardhana
AU - M. Capanu
AU - O. Basturk
AU - B. Rousseau
AU - Y. Wang
AU - J. Lihm
AU - N. Mohibullah
AU - V. Rolston
AU - E. Santos
AU - M. Reyngold
AU - A. Wei
AU - V. Balachandran
AU - M. H. Sherman
AU - N. Riaz
AU - C. Iacobuzio-Donahue
AU - B. Greenbaum
AU - E. M. O'Reilly
AU - W. Park
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752426
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752426v1
AB - 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.
ER -