HRS mediates tumor immune evasion by regulating proteostasis-associated interferon pathway activation

By sorting receptor tyrosine kinases into endolysosomes, the endosomal sorting complexes required for transport (ESCRTs) are thought to attenuate oncogenic signaling in tumor cells. Paradoxically, ESCRT members are upregulated in tumors. Here, we show that disruption of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a pivotal ESCRT component, inhibited tumor growth by promoting CD8+ T cell infiltration in melanoma and colon cancer mouse models. HRS ablation led to misfolded protein accumulation and triggered endoplasmic reticulum (ER) stress, resulting in the activation of the type I interferon pathway in an inositol-requiring enzyme-1α (IRE1α)/X-box binding protein 1 (XBP1)-dependent manner. HRS was upregulated in tumor cells with high tumor mutational burden (TMB). HRS expression associates with the response to PD-L1/PD-1 blockade therapy in melanoma patients with high TMB tumors. HRS ablation sensitized anti-PD-1 treatment in mouse melanoma models. Our study shows a mechanism by which tumor cells with high TMB evade immune surveillance and suggests HRS as a promising target to improve immunotherapy. To study the consequence of HGS inhibition, we performed shRNA knock-down (KD) experiments targeting several ESCRT members in B16 melanoma cell lines or mouse xenograft. We did RNA-seq for gene expression quantification. The B16 cell line samples consist of two batches. In the first batch, we constructed two groups: (1) control and (2) Hrs KD; each group has two replicates. In the second batch, we constructed two groups: (1) Hrs KD, and (2) control; each group has two replicates. The B16 tumor xenograft samples consist of two groups: (1) Hrs KD, and (2) control; each group has 5 replicates.