HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Clear cell renal cell carcinoma (ccRCC) is immunogenic despite low mutation rates.
• VHL gene inactivation leads to HIF transcription factor upregulation in ccRCC.
• A prior case showed donor T cells recognizing an ERV peptide in a cured ccRCC patient.

Purpose of the Study:

• To investigate the role of HIF-induced endogenous retroviruses (ERVs) in ccRCC immunogenicity.
• To determine if ERVs can elicit T cell responses in ccRCC.
• To explore the potential of ERVs for cancer immunotherapy.

Main Methods:

• Analysis of ERV expression in ccRCC tumors.
• Identification of HLA-bound peptides derived from ERVs.
• Assessment of T cell responses to ERV-derived peptides.
• Induction of ERV expression using HIF stabilizers in non-ccRCC tumors.

Main Results:

• Multiple ERVs are induced by HIF in ccRCC.
• HIF-induced ERVs are translated into HLA-bound peptides.
• These peptides can generate antigen-specific T cell responses.
• ERV expression is inducible in other tumors with HIF stabilizers.

Conclusions:

• HIF-induced ERVs are a source of ccRCC-specific antigens.
• ERVs can elicit anti-tumor T cell immunity.
• ERVs represent a promising target for ccRCC immunotherapy development.