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 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-27producing 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

Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer

“…When intratumorally CD8 + T cells are present they are usually exhausted and express checkpoints such as TIGIT ( 11 ), lymphocyte-activation gene 3 (LAG-3) and PD-1 ( 32 , 142 ). Recent research identified intratumoral exhausted T cells (PD-1 + Lag3 + Tox + ) as induced by myeloid cell derived IL-27 in an orthotopic model of PDA ( 143 ). Those intratumoral T cells not only produced less IFNγ and Granzyme B but also expressed more IL-10, thus contributing to immune suppression in an autocrine manner.…”

Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma

“…In contrast, it is largely absent on T cells infiltrating PDA. Most Lag3+Klrg1-T cells were exhausted whereas Lag3-Klrg1+ T cells were enriched intratumorally during a productive immunotherapy responses (23,64) and highly functional. Klrg1 is expressed on NK cells (65) and effector CD8 T cells during acute viral infection (66,67).…”

“…In contrast, T cells with identical peptide specificity remained largely functional in the spleens within the same tumor-bearing animals, indicating that the tumor and/or the TME drive T cell functional loss. Tox is elevated in both functional effector splenic CD8 T cells as well as intratumoral exhausted CD8 T cells (64). Early during tumor growth, intratumoral tumor-specific T cells co-express both Tox and Granzyme B and produce cytokines following antigen encounter.…”

“…We recently identified that intratumoral PD-1+Lag3+Tox+ exhausted tumor antigen-specific T cells not only lose functionality (e.g., IFNg, TNFa), they progressively express IL-10 specifically in the TME (64). As IL-10 is a regulatory cytokine (80), these data suggest that the TME instructs antigen-specific T cells to actually participate in immune suppression.…”

“…IL-27 receptor signaling can induce IL-10 (64) and promote a T cell exhaustion program (81). In orthotopic tumor bearing mice, intratumoral myeloid cells including granulocytes, TAMs, and dendritic cells (DC) upregulate IL-27 during tumorigenesis (64). Moreover, Il27ra -/mice had delayed tumor growth and a lower frequency of intratumoral antigenspecific T cells expressing Tox (64).…”