Expression of VISTA regulated via IFN-γ governs endogenous T-cell function and exhibits correlation with the efficacy of CD19 CAR-T cell treated B-malignant mice

• Published in: Journal for immunotherapy of cancer 2024-06, Vol.12 (6), p.e008364
• Main Authors: Tang, Donghai, Zhao, Li, Yan, Fen, Ren, Chunxiao, Xu, Kailin, Zhao, Kai
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens, CD19 - immunology; Antigens, CD19 - metabolism; B7 Antigens - metabolism; Basic Tumor Immunology; Bone marrow; Cell Line, Tumor; Cells; Disease Models, Animal; Flow cytometry; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Interferon-gamma - metabolism; Laboratory animals; Leukemia; Ligands; Lymphocyte Activation; Lymphocytes; Lymphoma; Medical research; Melanoma; Membrane Proteins; Mice; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; T-Lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Microenvironment
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-008364

BackgroundDespite continuous improvements in the new target and construction of chimeric antigen receptor (CAR)-T, relapse remains a significant challenge following CAR-T therapy. Tumor microenvironment (TME) strongly correlates with the efficacy of CAR-T therapy. V-domain Ig suppressor of T-cell activation (VISTA), which exerts a multifaceted and controversial role in regulating the TME, acts not only as a ligand on antigen-presenting cells but also functions as a receptor on T cells. However, the characteristics and underlying mechanisms governing endogenous T-cell activation by VISTA, which are pivotal for reshaping the TME, remain incompletely elucidated.MethodsThe immunocompetent B acute lymphoblastic leukemia (B-ALL), lymphoma, and melanoma murine models were employed to investigate the characteristics of endogenous T cells within the TME following CD19 and hCAIX CAR-T cell therapy, respectively. Furthermore, we examined the role of VISTA controlled by interferon (IFN)-γ signaling in regulating endogenous T-cell activation and functionality in B-ALL mice.ResultsWe demonstrated that the administration of CD19 CAR-T or hCAIX CAR-T cell therapy elicited augmented immune responses of endogenous T cells within the TME of B-ALL, lymphoma, and melanoma mice, thereby substantiating the efficacy of CAR-T cell efficacy. However, in the TME lacking IFN-γ signaling, VISTA levels remained elevated, resulting in attenuated cytotoxicity of endogenous T cells and reduced B-ALL recipient survival. Mice treated with CD19 CAR-T cells exhibited increased proportions of endogenous memory T cells during prolonged remission, which possessed the tumor-responsive capabilities to protect against B-ALL re-challenge. Compared with wild-type (WT) CAR-T treated mice, the administration of IFN-γ−/− CAR-T to both WT and IFN-γ−/− recipients resulted in a reduction in the numbers of endogenous CD4+ and CD8+ effectors, while exhibiting increased populations of naïve-like CD4+ T and memory CD8+ T cells. VISTA expression consistently remained elevated in resting or memory CD4+ T cells, with distinct localization from programmed cell death protein-1 (PD-1) expressing T subsets. Blocking the VISTA signal enhanced dendritic cell-induced proliferation and cytokine production by syngeneic T cells.ConclusionOur findings confirm that endogenous T-cell activation and functionality are regulated by VISTA, which is associated with the therapeutic efficiency of CAR-T and provides a promising thera