Agonistic anti-CD40 overcomes T cell exhaustion induced by chronic myeloid cell IL-27 production in a pancreatic cancer preclinical model

• Published in: The Journal of immunology (1950) Vol. 206; no. 6; pp. 1372 - 1384
• Main Authors: Burrack, Adam L., Rollins, Meagan R., Spartz, Ellen J., Mesojednik, Taylor D., Schmiechen, Zoe C., Raynor, Jackson F., Wang, Iris, Kedl, Ross M., Stromnes, Ingunn M.
• Format: Journal Article
• Language: English
• Published: 08.02.2021
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000765

Pancreatic cancer is a particularly lethal malignancy and resists immunotherapy. Here, using a preclinical pancreatic cancer murine model, we demonstrate a progressive decrease in IFNγ 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-bearing animals, promoted rejection following tumor re-challenge and correlated with a 2-log increase in pancreas-residing tumor-specific T cells. Interfering with Ifngr1 expression in non-tumor/host cells abrogated agonistic αCD40+αPD-L1 efficacy. In contrast, interfering with non-tumor/host cell Tnfrsf1a led to cure in 100% of animals following agonistic αCD40+αPD-L1 and promoted the formation of circulating central memory T cells rather than long-lived effector T cells. In summary, we identify a mechanistic basis for T cell exhaustion in pancreatic cancer and a feasible clinical strategy to overcome it.