Antitumor T-cell immunity contributes to pancreatic cancer immune resistance

Reham Ajina, Zoe X. Malchiodi, Allison A. Fitzgerald, Annie Zuo, Shangzi Wang, Maha Moussa, Connor J. Cooper, Yue Shen, Quentin R. Johnson, Jerry M. Parks, Jeremy C. Smith, Marta Catalfamo, Elana J. Fertig, Sandra A. Jablonski, Louis M. Weiner

Research output: Contribution to journalArticlepeer-review


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 languageEnglish (US)
Pages (from-to)386-400
Number of pages15
JournalCancer Immunology Research
Issue number4
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Immunology
  • Cancer Research


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