Agonistic CD40 mAb-Driven IL12 Reverses Resistance to Anti-PD1 in a T-cell-Rich Tumor.
In: Cancer research, Jg. 76 (2016-11-01), Heft 21, S. 6266-6277
Online
academicJournal
Zugriff:
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 PD1 hi T cells also contributes to insensitivity to this immune checkpoint 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 IL12 but not IL23, CD80/CD86/CD28, or CD70/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. Cancer Res; 76(21); 6266-77. ©2016 AACR.
(©2016 American Association for Cancer Research.)
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Agonistic CD40 mAb-Driven IL12 Reverses Resistance to Anti-PD1 in a T-cell-Rich Tumor.
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Autor/in / Beteiligte Person: | Ngiow, SF ; Young, A ; Blake, SJ ; Hill, GR ; Yagita, H ; Teng, MW ; Korman, AJ ; Smyth, MJ |
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Zeitschrift: | Cancer research, Jg. 76 (2016-11-01), Heft 21, S. 6266-6277 |
Veröffentlichung: | Baltimore, Md. : American Association for Cancer Research ; <i>Original Publication</i>: Chicago [etc.], 2016 |
Medientyp: | academicJournal |
ISSN: | 1538-7445 (electronic) |
DOI: | 10.1158/0008-5472.CAN-16-2141 |
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