Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune resistance in pancreatic cancer was induced in response to antitumor T-cell immune responses and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide evidence that T-cell–dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune resistance. Three KPC mouse models of pancreatic cancer were used: the mT3-2D (Krasþ/LSL-G12D; Trp53þ/LSL-R172H; Pdx1-Cre) subcutaneous and orthotopic models, as well as the KP1 (p48-CRE/LSL-Kras/Trp53flox/flox) subcutaneous model. KPC cancer cells were grown in immunocompetent and immunodeficient C57BL/6 mice and analyzed to determine the impact of adaptive immunity on malignant epithelial cells, as well as on whole tumors. We found that induced T-cell antitumor immunity, via signal transducer and activator of transcription 1 (STAT1), stimulated malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and altered intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA-approved drug ruxolitinib overcame these tumor-protective responses and improved anti–PD-1 therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.
Original language | English |
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Pages (from-to) | 386-400 |
Number of pages | 15 |
Journal | Cancer Immunology Research |
Volume | 9 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2021 |
Externally published | Yes |
Funding
and Tissue Shared Resource. R. Ajina was supported by King Saud bin Abdulaziz University for Health science (KSAU-HS) and the Saudi Arabian Cultural Mission (SACM). This research was sponsored by the Laboratory Directed Research and Development Program at Oak Ridge National Laboratory (ORNL), which is managed by UT-Battelle, LLC, for the U.S. Department of Energy (DOE) under contract number DE-AC05-00OR22725. C.J. Cooper was supported by NIH/National Institute of General Medical Sciences (NIGMS) Initiative for Maximizing Student Development (IMSD) grant R25GM086761 (J.M. Parks). This research was supported by Lustgarten Foundation, the Emerson Foundation (640183), and the Allegheny Foundation (E.J. Fertig). This research was supported by Leidos Biomedical Research, Inc. and has been funded in whole or in part with federal funds from the NCI, NIH, under This research was supported by NCI R01 CA50633 (L.M. Weiner) and NIH/NCI grant P30-CA051008 (L.M. Weiner). Lombardi Comprehensive Cancer Center Shared Resources supporting this study include the following: the Genomics and Epigenomics Shared Resource, the Flow Cytometry and Cell Sorting Shared Resource, the Tissue Culture Shared Resource, the Proteomics and Metabolomics Shared Resource, the Biostatistics and Bioinformatics Shared Resource, and the Histopathology E.J. Fertig reports grants from NIH/NCI, Lustgarten Foundation, Allegheny Foundation, and NIH/National Institute of Dental and Craniofacial Research (NIDCR) during the conduct of the study; a grant from AACR/SU2C outside the submitted work; and is on the scientific advisory board for Viosera Therapeutics. L.M. Weiner reports grants from NCI during the conduct of the study, as well as personal fees from Celldex Therapeutics, Jounce Therapeutics, Tessa Therapeutics, Samyang BioPharma USA, Menarini, and Molecular Templates, personal fees and other from Cytomx Therapeutics (scientific advisory board, stock options) and Immunome (scientific advisory board, stock options), other from Targeted Diagnostics & Therapeutics (shareholder), Klus Pharmaceuticals (scientific advisory board), and Xiconic (scientific advisory board), and grants from Bioexcel Therapeutics outside the submitted work. No disclosures were reported by the other authors.