The lipid-metabolic enzyme HSD17B12 drives lysosomal degradation of PD-L1 potentiating anti-tumor immunity in a mouse model

TL;DR

A metabolic enzyme called HSD17B12 helps break down PD-L1, a protein that helps tumors avoid immune attacks, and a peptide based on HSD17B12 can reduce tumor growth in mice.

Contribution

HSD17B12 is shown to regulate PD-L1 degradation via lysosomes, and a derived peptide is developed to enhance anti-tumor immunity.

Findings

HSD17B12 promotes lysosome-dependent degradation of PD-L1 via VAC14 and ESCRT complexes.

HSD17B12 deficiency leads to PD-L1 accumulation and reduced T cell cytotoxicity.

An HSD17B12-derived peptide suppresses tumor growth in a mouse model.

Abstract

The high prevalence of cancer immunotherapy resistance, coupled with substantial tumor heterogeneity, underscores the urgent need for innovative therapeutic targets. A deeper understanding of immunoregulatory mechanisms would provide new targets and combination therapeutic strategies for tumor therapy. In this study, we demonstrate that HSD17B12 enhances anti-tumor immunity and represents a promising therapeutic target. Mechanistically, HSD17B12 promotes lysosome-dependent degradation of PD-L1 via the VAC14 and ESCRT complexes across various malignancies, regardless of its 3-ketoacyl-CoA reductase activity. HSD17B12-deficient cells displayed PD-L1 accumulation in both tumor cells and exosomes, reducing T cell-mediated cytotoxicity. Notably, we found a significant negative correlation between HSD17B12 and PD-L1 expression in colorectal cancer tissues. Furthermore, high HSD17B12 expression in CRC correlated with increased infiltration of cytotoxic T cells. Based on these findings, we designed a peptide, HSD-CC1-NPGY, which effectively reduces PD-L1 expression in cells and suppresses tumor growth in a mouse model. Overall, our results establish HSD17B12 as an important regulator of anti-tumor immunity and a promising therapeutic target for cancer treatment.

Cancer immunotherapy faces widespread resistance driven by tumor heterogeneity and immune evasion through mechanisms like PD-L1 suppression. This study identifies the metabolic enzyme HSD17B12 as a regulator of PD-L1 degradation and shows that an HSD17B12-derived peptide boosts anti-tumor immunity in a mouse model.

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