RESUMO
PURPOSE: The limited efficacy of chimeric antigen receptor (CAR) T-cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3.CAR T cells with several solid cancer types. EXPERIMENTAL DESIGN: We evaluated B7-H3 expression in many human solid cancer and normal tissue samples. The efficacy of the combinatorial therapy with B7-H3.CAR T cells and the deacetylase inhibitor SAHA with several solid cancer types and the potential underlying mechanisms were characterized with in vitro and ex vivo experiments. RESULTS: B7-H3 is expressed in most of the human solid tumor samples tested, but exhibits a restricted expression in normal tissues. B7-H3.CAR T cells selectively killed B7-H3 expressing human cancer cell lines in vitro. A low dose of SAHA upregulated B7-H3 expression in several types of solid cancer cells at the transcriptional level and B7-H3.CAR expression on human transgenic T-cell membrane. In contrast, the expression of immunosuppressive molecules, such as CTLA-4 and TET2, by T cells was downregulated upon SAHA treatment. A low dose of SAHA significantly enhanced the antitumor activity of B7-H3.CAR T cells with solid cancers in vitro and ex vivo, including orthotopic patient-derived xenograft and metastatic models treated with autologous CAR T-cell infusions. CONCLUSIONS: Our results show that our novel strategy which combines SAHA and B7-H3.CAR T cells enhances their therapeutic efficacy with solid cancers and justify its translation to a clinical setting.
Assuntos
Antígenos B7 , Inibidores de Histona Desacetilases/uso terapêutico , Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Terapia Combinada , Humanos , Camundongos , Células Tumorais CultivadasRESUMO
Repulsive guidance molecules comprise a group of proteins that play an important role in carcinogenesis through interactions with their receptors, but their function in oral squamous cell carcinoma (OSCC) is unclear. Here, we investigated the potential role of the RGM family members in oral cancer pathogenesis. Our study showed that only RGMA was significantly downregulated in the OSCC tissues analyzed by TCGA and validated this finding in OSCC cells. The decreased expression of RGMA was strongly associated with the T stage and with poor prognosis. The ectopic expression of RGMA significantly inhibited the proliferation of OSCC cells both in vitro and in vivo. Moreover, we confirmed that RGMA was a target of miR-210-3p in OSCC and miR-210-3p overexpression contributed to the acceleration of OSCC growth. Further experiments revealed that HIF1A specifically interacted with the promoter of miR-210-3p and enhanced its expression. In summary, our research indicates that RGMA is regulated by the HIF1A/miR-210-3p axis and inhibits OSCC cell proliferation; thus, in the future, the development of therapies that target the HIF1A/miR-210-3p/RGMA axis may aid in the treatment of aggressive cancers.