Increased activation and function but also increased T cell loss from activation induced cell death by PD-1 inhibition

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B613
Abstract ID: 5738

Presenting Author:
Michael Sheng , Graduate Student Researcher at Univ. of California, Davis, Med. Ctr.

Abstract:

PD-1 is upregulated on T cells during TCR engagement and inhibits effector function and the function of memory T cells. Inhibition of PD-1/PD-L1 interactions reverses T cell exhaustion resulting in increased anti-tumor effects. Chimeric antigen receptor (CAR) T cells have also been shown to possess strong anti-tumor effects yet PD-1/PDL-1 inhibition has yielded negative or equivocal data in CAR T cell therapy. We examined the effects of PD-1 on TCR or CAR-triggered T cells using in vitro and in vivo assays with mouse, canine, and human T cells. T cells from PD-1-/- mice demonstrated greater activation upon stimulation in vitro yet also later increased apoptosis and cell loss. These results also were observed in vivo with anti-PD-1 on T cells. Canine CAR T cells engineered to have a PD-1/CD28 switch affecting signaling also demonstrated increased activity but increased T cell loss with reduced anti-tumor effects in a tumor xenograft model. Human T or CAR T cells placed into immunodeficient mice and treated with anti-PD-1 also exhibited increased activation and proliferation but later had marked apoptosis and loss of engraftment correlating with reduced anti-tumor efficacy. Our results indicate PD-1 protects T cells across species from AICD upon strong TCR-mediated stimulation. While PD-1 inhibition may potentially increase T cell function resulting in initially increased anti-tumor effects it may ultimately result in lack of sustained function and impaired long-term efficacy.