| First Author | Burrack AL | Year | 2021 |
| Journal | J Immunol | Volume | 206 |
| Issue | 6 | Pages | 1372-1384 |
| PubMed ID | 33558374 | Mgi Jnum | J:306132 |
| Mgi Id | MGI:6515445 | Doi | 10.4049/jimmunol.2000765 |
| Citation | Burrack AL, et al. (2021) CD40 Agonist Overcomes T Cell Exhaustion Induced by Chronic Myeloid Cell IL-27 Production in a Pancreatic Cancer Preclinical Model. J Immunol 206(6):1372-1384 |
| abstractText | 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-gamma 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 alphaCD40 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 alphaCD40+alphaPD-L1 cured 63% of tumor-bearing animals, promoted rejection following tumor rechallenge, and correlated with a 2-log increase in pancreas-residing tumor-specific T cells. Interfering with Ifngr1 expression in nontumor/host cells abrogated agonistic alphaCD40+alphaPD-L1 efficacy. In contrast, interfering with nontumor/host cell Tnfrsf1a led to cure in 100% of animals following agonistic alphaCD40+alphaPD-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. |
