Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer

Hilmi, M.; Schoenfeld, J. D.; McKerrow, W.; Elhanati, Y.; O'Connor, C. A.; Umeda, S.; Lecomte, N.; Melchor, J. P.; Cardenas, A.; Lao, M.; Nasca, V.; Karnoub, E.-R.; Tezcan, N.; Tarcan, Z.; Chou, J. F.; Sharma, R.; Song, J.; May, M.; Balogun, F.; Yu, K. H.; Soares, K.; Reiche, C.; Milighetti, M.; Pe'er, D.; Vardhana, S. A.; Capanu, M.; Basturk, O.; Rousseau, B.; Wang, Y.; Lihm, J.; Mohibullah, N.; Rolston, V.; Santos, E.; Reyngold, M.; Wei, A.; Balachandran, V.; Sherman, M. H.; Riaz, N.; Iacobuzio-Donahue, C.; Greenbaum, B.; O'Reilly, E. M.; Park, W.

doi:10.64898/2026.09.17.752426

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bioRxiv · 10.64898/2026.09.17.752426

Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer

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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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Hilmi, M., Schoenfeld, J. D., McKerrow, W., Elhanati, Y., O'Connor, C. A., Umeda, S., Lecomte, N., Melchor, J. P., Cardenas, A., Lao, M., Nasca, V., Karnoub, E.-R., Tezcan, N., Tarcan, Z., Chou, J. F., Sharma, R., Song, J., May, M., Balogun, F., Yu, K. H., Soares, K., Reiche, C., Milighetti, M., Pe'er, D., Vardhana, S. A., Capanu, M., Basturk, O., Rousseau, B., Wang, Y., Lihm, J., Mohibullah, N., Rolston, V., Santos, E., Reyngold, M., Wei, A., Balachandran, V., Sherman, M. H., Riaz, N., Iacobuzio-Donahue, C., Greenbaum, B., O'Reilly, E. M., Park, W.. 2026-09-18. Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer. https://doi.org/10.64898/2026.09.17.752426

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