CD40 Agonist Overcomes T Cell Exhaustion Induced by Chronic Myeloid Cell IL-27 Production in a Pancreatic Cancer Preclinical Model.

ABSTRACT: Pancreatic cancer is a particularly lethal malignancy that resists immunotherapy. In this study, using a preclinical pancreatic cancer murine model, we demonstrate a progressive decrease in IFN-γ and granzyme B and a concomitant increase in Tox and IL-10 in intratumoral tumor-specific T cells. Intratumoral myeloid cells produced elevated IL-27, a cytokine that correlates with poor patient outcome. Abrogating IL-27 signaling significantly decreased intratumoral Tox⁺ T cells and delayed tumor growth yet was not curative. Agonistic αCD40 decreased intratumoral IL-27-producing myeloid cells, decreased IL-10-producing intratumoral T cells, and promoted intratumoral Klrg1⁺Gzmb⁺ short-lived effector T cells. Combination agonistic αCD40+αPD-L1 cured 63% of tumor-be

SUBMITTER: Burrack AL 

PROVIDER: S-EPMC7977703 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature