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IAP inhibitor, Embelin increases VCAM-1 levels on the endothelium, producing lymphocytic infiltration and antitumor immunity.

ABSTRACT: There is an increasing unmet need for successful immunotherapeutic interventions. Lymphocyte extravasation via tumor tissue endothelial cells (TECs) is required for lymphocyte infiltration into tumor sites. This study aimed to investigate the clinical significance of dysfunctional TECs in pancreatic ductal adenocarcinoma (PDAC) and identify chemical compounds that boost tumor-infiltrating lymphocyte (TIL) numbers. We performed immunohistochemical detection and clinicopathological analysis of VCAM-1 on TECs, which is essential for lymphocyte trafficking. We characterized the gene expression profiles of TECs from fresh PDAC tissues. We isolated compounds that upregulated VCAM-1 and E-selectin expression in TECs and examined their biological activities. Compared to endothelial cells from chronic pancreatitis tissue, TECs showed significantly lower VCAM-1 and E-selectin expression and significant weaknesses in lymphocyte adhesion and transmigration, resulting in decreased T cell infiltration around vessels. Patients with a relatively high percentage of VCAM-1⁺ vessels among all vessels in PDAC tissue had an improved prognosis. A bioinformatics survey demonstrated that TNFR1 signaling was involved in abnormal VCAM-1 and E-selectin expression in TECs. We screened compounds affecting TNFR1 signaling, and the IAP inhibitor, Embelin, induced these molecules on TECs and enhanced T cell adhesion to TECs and transmigration. Furthermore, in vivo, Embelin enhanced tumor-infiltrating T cell numbers, leading to an antitumor immune response. Embelin accelerates TIL infiltration and the antitumor immune response by recovering VCAM-1 expression in TECs. Our strategy may be a therapeutic approach for accelerating the immunotherapeutic response in immune-quiescent tumors, leading to clinical trials' success.

SUBMITTER: Nakajima K

PROVIDER: S-EPMC7595596 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:As a safe, feasible, and inexpensive dietary intervention, fasting-mimicking diet (FMD) exhibits excellent antitumor efficacy by regulating metabolism and boosting antitumor immunity. A better understanding of the specific mechanisms underlying the immunoregulatory functions of FMD could help improve and expand the clinical application of FMD-mediated immunotherapeutic strategies. In this study, we aimed to elucidate the role of metabolic reprogramming induced by FMD in activation of antitumor immunity against colorectal cancer. Single-cell RNA sequencing analysis of intratumoral immune cells revealed that tumor-infiltrating IgA+ B cells were significantly reduced by FMD treatment, leading to the activation of antitumor immunity and tumor regression in murine colorectal cancer models. Mechanistically, FMD delayed tumor growth by repressing B-cell class switching to IgA. Therefore, FMD-induced reduction of IgA+ B cells overcame the suppression of CD8+ T cells. The immunoregulatory and antitumor effects of FMD intervention were reversed by IgA+ B-cell transfer. Moreover, FMD boosted fatty acid oxidation (FAO) to trigger RUNX3 acetylation, thus inactivating Cα gene transcription and IgA class switching. IgA+ B-cell expansion was also impeded in patients placed on FMD, while B-cell expression of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme of FAO, was increased. Furthermore, CPT1A expression was negatively correlated with both IgA+ B cells and IgA secretion within colorectal cancer. Together, these results highlight that FMD holds great promise for treating colorectal cancer. Furthermore, the degree of IgA+ B cell infiltration and FAO-associated metabolic status are potential biomarkers for evaluating FMD efficacy.SignificanceMetabolic reprogramming of B cells induced by fasting-mimicking diet suppresses IgA class switching and production to activate antitumor immunity and inhibit tumor growth. See related commentary by Bush and Perry, p. 3493.

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IAP inhibitor, Embelin increases VCAM-1 levels on the endothelium, producing lymphocytic infiltration and antitumor immunity.

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