Agonistic anti-CD40 overcomes T cell exhaustion induced by chronic myeloid cell IL-27 production in a pancreatic cancer preclinical model
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 mye...
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Published in | The Journal of immunology (1950) Vol. 206; no. 6; pp. 1372 - 1384 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
08.02.2021
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Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | A.L.B. and I.M.S designed the study, analyzed the data, and wrote the manuscript. A.L.B., M.R.R., E.J.S., T.D.M, Z.C.S, J.F.R. and I.W. conducted experiments and analyzed data. R.M.K. provided expertise on IL-27 signaling and the IL-27 reporter strain. I.M.S is guarantor of the study. AUTHOR CONTRIBUTIONS |
ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.2000765 |