Agonistic CD40 mAb-driven IL12 reverses resistance to anti-PD1 in a T-cell-rich tumor

Shin Foong Ngiow, Arabella Young, Stephen J. Blake, Geoffrey R. Hill, Hideo Yagita, Michele W.L. Teng, Alan J. Korman, Mark J. Smyth

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71 Citations (Scopus)


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 PD1hi 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 PD1hi T cells into PD1lo 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 PD1hi T cells to PD1lo T cells, with clinical implications in the management of anti-PD1 refractory patients.

Original languageEnglish
Pages (from-to)6266-6277
Number of pages12
JournalCancer Research
Issue number21
Publication statusPublished or Issued - 1 Nov 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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