S. Kang, M. Parikh, L. Pappas, J. L. Koenig, L. Bi, B. Y. Yeap, N. Carzo, T. M. Grillo, I. Baiev, O. Asupoto, A. Lako, I. Gushterova, T. J. Carmona-LaSalle, A. L. Gonye, E. M. Blaum, J. W. Clark, C. D. Weekes, J. N. Allen, L. S. Blaszkowsky, D. P. Ryan, J. M. Cleary, J. D. Mancias, B. L. Schlechter, S. E. Slater, J. Y. Wo, T. A. Abrams, S. M. Corsello, J. W. Franses, M. Giannakis, J. A. Meyerhardt, M. B. Yurgelun, C. Bolton, H. J. Roberts, S. von Fedak, L. C. Drapek, B. M. Wolpin, D. Pe'er, D. T. Ting, M. Sade-Feldman, T. S. Hong, N. Hacohen, A. Parikh
Microsatellite stable (MSS) pancreatic ductal adenocarcinoma (PDAC) is refractory to immune checkpoint blockade. We conducted a single-arm phase II trial (NCT04361162) combining nivolumab, ipilimumab and radiation therapy to treat patients with pre-treated metastatic MSS PDAC (n=30). We integrated longitudinal profiling of 32 pre- and on-treatment tumor biopsies from 22 patients, yielding 245,529 single-nucleus and 128,295 single-cell transcriptomes including 27,215 T-cells with paired TCR clonotypes, as well as Visium spatial transcriptomics from 13 biopsies, and peripheral blood TCR-sequencing from 25 patients. While clinical activity was limited overall, one patient achieved a durable complete response with no evidence of disease 4 years after trial enrollment. This response was marked by a therapy-associated shift in the state composition of pre-existing CD8 T cell clonotypes from GZMK+ to exhausted and predicted tumor-reactive states, durable maintenance of associated clonotypes in the blood after 1 year, interferon-polarized macrophage and fibroblast programs, and high levels of ACKR1+ venous endothelium. Across independent PDAC cohorts, high ACKR1 expression was associated with improved survival, greater intratumoral TCR richness and clonality, and increased tumor-blood TCR sharing. These findings suggest that productive immunotherapy responses in PDAC require not only tumor-reactive T cells, but also a stromal-vascular niche capable of supporting their recruitment, recirculation and persistence. This may have implications for the design of future immunotherapy and vaccine strategies for PDAC.