Anti-PD-L1 antibody limits the survival of activated CAR T cells by disrupting the PD-L1/CD80 cis-heterodimer
Abstract
Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematologic malignancies but remain less efficacious in solid tumors. While PD-L1 blockade is widely used to counter tumor immune evasion, its direct effects on activated T cells, which also express PD-L1 and may engage in PD-L1/CD80 cis-interactions, remain largely unexplored. To investigate this, we blocked PD-L1 by engineering CAR T cells that secrete PD-L1-blocking single-chain variable fragment (scFv) antibodies derived from atezolizumab. Secretion of the scFv conferred no benefit: 4-1BB-based CAR T cells accumulated less upon repeated antigen stimulation, and CD28-based CAR T cells killed less efficiently when effector cells were limiting. Mechanistically, PD-L1 and CD80 form a cis-heterodimer on T cells that is disrupted by PD-L1 blockade, rendering CD80 susceptible to CTLA-4-mediated depletion and impairing CD28 co-stimulation. Consistent with this model, exogenous atezolizumab reduced CD80 expression and T cell viability, while CTLA-4 blockade with ipilimumab restored CD80 levels and rescued survival. These findings were corroborated by structural modeling demonstrating that atezolizumab disrupts the PD-L1/CD80 complex, and were reproduced in unmodified T cells and across both CD28- and 4-1BB-based CARs. Together, our findings uncover a T cell-intrinsic vulnerability to PD-L1 inhibitors that warrants consideration when PD-L1 blockade is combined with adoptive T cell therapy.
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BibTeX
@article{li2026antipdl1,
title = {{Anti-PD-L1 antibody limits the survival of activated CAR T cells by disrupting the PD-L1/CD80 cis-heterodimer}},
author = {Sin-Syue Li and Markus Barden and Hong Pan and Dennis Christoph Harrer and Marcell Kaljanac and Valerie Bezler and Moritz Ertelt and Clara Schoeder and Tsai-Yun Chen and Hinrich Abken},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1906848},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906848},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Anti-PD-L1 antibody limits the survival of activated CAR T cells by disrupting the PD-L1/CD80 cis-heterodimer
AU - Sin-Syue Li
AU - Markus Barden
AU - Hong Pan
AU - Dennis Christoph Harrer
AU - Marcell Kaljanac
AU - Valerie Bezler
AU - Moritz Ertelt
AU - Clara Schoeder
AU - Tsai-Yun Chen
AU - Hinrich Abken
PY - 2026
DA - 2026/11/02
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1906848
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906848
AB - Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematologic malignancies but remain less efficacious in solid tumors. While PD-L1 blockade is widely used to counter tumor immune evasion, its direct effects on activated T cells, which also express PD-L1 and may engage in PD-L1/CD80 cis-interactions, remain largely unexplored. To investigate this, we blocked PD-L1 by engineering CAR T cells that secrete PD-L1-blocking single-chain variable fragment (scFv) antibodies derived from atezolizumab. Secretion of the scFv conferred no benefit: 4-1BB-based CAR T cells accumulated less upon repeated antigen stimulation, and CD28-based CAR T cells killed less efficiently when effector cells were limiting. Mechanistically, PD-L1 and CD80 form a cis-heterodimer on T cells that is disrupted by PD-L1 blockade, rendering CD80 susceptible to CTLA-4-mediated depletion and impairing CD28 co-stimulation. Consistent with this model, exogenous atezolizumab reduced CD80 expression and T cell viability, while CTLA-4 blockade with ipilimumab restored CD80 levels and rescued survival. These findings were corroborated by structural modeling demonstrating that atezolizumab disrupts the PD-L1/CD80 complex, and were reproduced in unmodified T cells and across both CD28- and 4-1BB-based CARs. Together, our findings uncover a T cell-intrinsic vulnerability to PD-L1 inhibitors that warrants consideration when PD-L1 blockade is combined with adoptive T cell therapy.
SN - 1664-3224
ER -