Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers

• Published in: Journal for immunotherapy of cancer Vol. 11; no. 1; p. e003837
• Main Authors: Ba, Hongping, Dai, Zigang, Zhang, Zunyue, Zhang, Peng, Yin, Bingjiao, Wang, Jing, Li, Zhuoya, Zhou, Xiaoxi
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.01.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Antigens; Breast cancer; Breast neoplasms; Cancer; Chimeric antigen receptor; Clinical trials; Cloning; Cytotoxicity; Flow cytometry; Humans; Hyperplasia; Immune Cell Therapies and Immune Cell Engineering; Immunotherapy; Interferon-gamma; Leukemia; Lymphocytes; Metastasis; Mice; Peptides; Programmed Cell Death 1 Receptor; Programmed death-1 monoclonal antibody; Proteins; Receptors, Chimeric Antigen; T-Lymphocytes; Transmembrane tumor necrosis factor-alpha; Triple Negative Breast Neoplasms - therapy; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumors; California; United States > US; China; Germany; New Jersey; Breast neoplasms; Chimeric antigen receptor; Transmembrane tumor necrosis factor-alpha; Programmed death-1 monoclonal antibody; Immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-003837

BackgroundOur previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies.MethodsWe generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo.ResultsOur tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy.ConclusionOur findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC.