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