| Autor: |
John S Davies, Farrah Karimipour, Ling Zhang, Nisha Nagarsheth, Scott Norberg, Carylinda Serna, Julius Strauss, Shinheng Chiou, James L Gulley, Christian S Hinrichs |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Journal for immunotherapy of cancer. 10(7) |
| ISSN: |
2051-1426 |
| Popis: |
BackgroundCell therapy has shown promise in the treatment of certain solid tumors, but its efficacy may be limited by inhibition of therapeutic T cells by the programmed cell death protein-1 (PD-1) receptor. Clinical trials are testing cell therapy in combination with PDCD1 disruption or PD-1-axis blockade. However, preclinical data to support these approaches and to guide the treatment design are lacking.MethodsMechanisms of tumor regression and interaction between cell therapy and PD-1 blockade were investigated in congenic murine tumor models based on targeting established, solid tumors with T-cell receptor T cells directed against tumor-restricted, non-self antigens (ie, tumor neoantigens).ResultsIn solid tumor models of cell therapy, PD-1 blockade mediated a reproducible but non-synergistic increase in tumor regression following adoptive T-cell transfer. Tumor regression was associated with increased tumor infiltration by endogenous T cells but not by transferred T cells. The effect was independent of PD-1 receptor expression by transferred T cells and was dependent on the endogenous T-cell repertoire and on tumor antigenicity. PD-1 blockade primarily induced cell state changes in endogenous tumor-antigen-specific T cells rather than transferred T cells.ConclusionsTogether, these findings support the concept that PD-1 blockade acts primarily through endogenous rather than transferred T cells to mediate a non-synergistic antitumor effect in solid tumor cell therapy. These findings have important implications for strategies to leverage PD-1 receptor disruption or blockade to enhance the efficacy of cell therapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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