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

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Endosomal sorting complexes required for transport (ESCRTs) typically attenuate oncogenic signaling.
• Paradoxically, ESCRT members, including hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), are upregulated in tumors.
• The precise role of HRS in tumor immune evasion remains unclear.

Purpose of the Study:

• To investigate the role of HRS in tumor growth and immune evasion.
• To explore the therapeutic potential of targeting HRS in cancer immunotherapy.

Main Methods:

• Utilized melanoma and colon cancer mouse models with HRS disruption.
• Analyzed protein accumulation, endoplasmic reticulum (ER) stress, and type I interferon pathway activation.
• Assessed CD8+ T cell infiltration and response to anti-PD-1 therapy.
• Correlated HRS expression with tumor mutational burden (TMB) and patient response to PD-L1/PD-1 blockade.

Main Results:

• HRS disruption inhibited tumor growth and increased CD8+ T cell infiltration.
• HRS ablation induced misfolded protein accumulation, ER stress, and type I interferon pathway activation via IRE1α/XBP1.
• HRS was upregulated in high TMB tumors and associated with immunotherapy response.
• HRS inhibition sensitized tumors to anti-PD-1 treatment in mouse models.

Conclusions:

• Tumor cells with high TMB may evade immune surveillance through HRS-mediated mechanisms.
• Targeting HRS can enhance anti-PD-1 immunotherapy efficacy, particularly in high TMB cancers.
• HRS represents a promising therapeutic target for improving cancer immunotherapy outcomes.