Year: 2021
Type: article
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 evasion in pancreatic cancer is induced in response to T cell-based immune selection pressure, and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide the first evidence that T cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune evasion. mT3-2D cells derived from a Kras +/ LSL-G12D ; Trp53 +/ LSL-R172H ; Pdx1-Cre (KPC) mouse model of pancreatic cancer were grown in immunocompetent and immunodeficient C57BL/6 mice, and analyzed to determine the impacts of adaptive immunity specifically on malignant epithelial cells as well as on whole tumors. We found that immune selection pressure, via signal transducer and activator of transcription 1 (STAT1), stimulates malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and alters intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA approved drug, ruxolitinib, overcomes these tumor-protective responses and improves anti-PD1 antibody therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.
Source: Cancer Immunology Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Energy, Battelle, Lustgarten Foundation, Leidos, UT-Battelle, King Saud bin Abdulaziz University for Health Science, National Institutes of Health, Saudi Arabian Cultural Mission, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Laboratory Directed Research and Development, Oak Ridge National Laboratory
Awards: G1026679911, G1334669072, G1645119126, G166562317, G203625172, G2584197162, Therapeutic/Mechanistic Role of Ape1 in Germ Cell Tumors, G2988778103, G3015188539, G313676650, G3503792436, G3539553811, G386607036, G4382062407, G4423657506, The impact of HIV driven T cell immune activation in angiogenic CD8 T cell function: the role of PAR1 signaling, G5726405315, G574648691, G5888954722, G5916996170, Antibody-Targeted Cancer Immunotherapy, G675320460, G7734004253, SPORE in Gastrointestinal Cancers, Program for Excellence and Equity Research, G8906985441, G8943143067, G9000226715, Georgetown University Lombardi Comprehensive Cancer Center Support Grant
OpenAlex ID: W3121869337