The durability and efficacy of anti-human PD1 monoclonal antibodies (PD1 mAb) vary across different malignancies. Although an absence of tumor-infiltrating cytotoxic T lymphocytes has been identified as a cause for resistance to PD1 mAb, the presence of intratumor exhausted PD1hi T cells also contributes to insensitivity to thisimmunecheckpoint therapy. In this study, we used mouse tumor models of PD1 mAb resistance that harbored PD1(hi) T cells and flow cytometry analysis of tumor-infiltrating leukocytes immediately post-therapy as a screening platform to identify agents that could resensitize T cells to PD1 blockade. We showed that an agonistic anti-CD40 mAb converted PD1(hi) T cells into PD1(lo) T cells, reversing phenotypic T-cell exhaustion and allowing the anti-PD1 refractory tumors to respond to anti-PD1 therapy. PD1 downmodulation by anti-CD40 mAb relied upon IL12but not IL23, CD80/CD86/CD28, orCD70/CD27. Consistent with a role for regulatory T cells (Treg) in promoting T-cell exhaustion, we also showed that intratumor Treg presented with a less activated and attenuated suppressive phenotype, marked by reductions in CTLA4 and PD1. Similar to anti-CD40 mAb, anti-CTLA4 mAb also lowered intratumor T-cell PD1 expression. Our study provides a proof-of-principle framework to systematically identify immune conditioning agents able to convert PD1(hi) T cells to PD1(lo) T cells, with clinical implications in the management of anti-PD1 refractory patients.
| Authors | Ngiow, Shin Foong; Young, Arabella; Blake, Stephen J.; Hill, Geoffrey R.; Yagita, Hideo; Teng, Michele W. L.; Korman, Alan J.; Smyth, Mark J. |
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| Journal | CANCER RESEARCH |
| Pages | 6266-6277 |
| Volume | 76 |
| Date | 1/11/2016 |
| Grant ID | |
| Funding Body | NHMRC |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1158/0008-5472.CAN-16-2141 |
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