Journal
CANCER IMMUNOLOGY RESEARCH
Volume 7, Issue 2, Pages 269-281Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-18-0222
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Funding
- American Cancer Society [PF-14-053-01]
- NIH [5R01CA102577, T32AI078903]
- Providence Medical Foundation
- MedImmune
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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 bio-energetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells.
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