Abstract
BackgroundChimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1.MethodsHere, we designed a dominant-negative form of PD-1, dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain.ResultsdPD1z T and CARPD-L1z T cells efficiently lysed PD-L1+ tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells.ConclusionsIn conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.
Highlights
Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cellderived malignancy
Tumor cells To redirect T cells attack tumor cells expressing PD-L1, we designed a dominant-negative form of PD-1, dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PDL1, CARPD-L1z, a vector with a high-affinity Single-chain fragment variable (scFv) against human PD-L1
Both dPD1z T and CARPD-L1z T cells are capable of dPD1z T and CARPD-L1z T cells inhibited the growth of multiple types of tumors in vivo The anti-tumor efficacy of dPD1z T and CARPD-L1z T cells were subsequently examined in a cell line-derived xenografts (CDX)
Summary
Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cellderived malignancy. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1. Chimeric antigen receptor T cells (CAR-T cells) have emerged as a promising therapy for treating B cellderived malignancy [1, 2]. PD-1, a well-characterized immune checkpoint molecule, plays pivotal roles in regulating T cell function. PD1 upregulation is associated with T cell exhaustion that inhibits T cell functions upon binding to its ligands, such as PD-L1 and PD-L2 [23]. PD-L1 is widely expressed in various solid tumors [24,25,26]. Its expression is influenced by (2020) 8:19
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