Late-stage tumor regression after PD-L1 blockade plus a concurrent OX40 agonist

Fanny Polesso, Andrew D. Weinberg, Amy Moran

Research output: Contribution to journalArticle

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Abstract

The protective capability of tumor antigen-specific T cells is regulated by costimulatory and inhibitory signals. Current approaches in cancer immunotherapy seek to restore the function of unresponsive T cells by blocking inhibitory pathways. In contrast, providing exogenous costimulatory signals to T cells also enhances antitumor functionality. By combining these two clinical approaches, we demonstrate the synergy of targeting PD-L1 together with the costimulatory molecule OX40, to enhance antitumor immunity. Concurrently blocking PD-L1 and providing a costimulatory agonist to OX40 increased the presence and functionality of tumor antigen-specific CD8+ T cells with simultaneous enhancement of T-helper type 1 (Th1)-skewed CD4+ T cells. This shift was functionally supported by increased glucose metabolism of antigen-specific CD8+ T cells and the acquisition of granzyme B by regulatory T cells. Together, this mechanism promoted tumor regression of late-stage tumors beyond that achieved by either blockade as monotherapy. These findings indicate that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells.

Original languageEnglish (US)
Pages (from-to)269-281
Number of pages13
JournalCancer Immunology Research
Volume7
Issue number2
DOIs
StatePublished - Feb 1 2019

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T-Lymphocytes
Neoplasms
Neoplasm Antigens
CD8 Antigens
Granzymes
Regulatory T-Lymphocytes
Immunotherapy
Energy Metabolism
Immunity
Glucose

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Late-stage tumor regression after PD-L1 blockade plus a concurrent OX40 agonist. / Polesso, Fanny; Weinberg, Andrew D.; Moran, Amy.

In: Cancer Immunology Research, Vol. 7, No. 2, 01.02.2019, p. 269-281.

Research output: Contribution to journalArticle

Polesso, Fanny ; Weinberg, Andrew D. ; Moran, Amy. / Late-stage tumor regression after PD-L1 blockade plus a concurrent OX40 agonist. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 2. pp. 269-281.
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