STAT1-Deficient HPV E6/E7-Associated Cancers Maintain Host Immunocompetency against Therapeutic Intervention

Area of Science:

• Oncology
• Immunology
• Virology

Background:

• Human papillomavirus (HPV) causes significant global cancer burden, including cervical, oropharyngeal, and anal cancers.
• HPV-induced oncogenesis involves the Janus protein tyrosine kinase (JAK)/STAT signaling pathway, with STAT3's role established, but STAT1's role in tumor formation remains unclear.

Purpose of the Study:

• To investigate the role of STAT1 in HPV-associated oral tumorigenesis using STAT1 knockout (STAT1-/-) mice.
• To evaluate the therapeutic efficacy of an HPV DNA vaccine (CRT/E7) in a STAT1-deficient tumor microenvironment.

Main Methods:

• Utilized a spontaneous HPV E6/E7-expressing oral tumor model in STAT1-/- mice.
• Administered the candidate HPV DNA vaccine CRT/E7 to assess therapeutic response.
• Conducted immunological analyses to characterize T cell populations and activity.
• Performed whole-cell tumor challenge experiments to evaluate tumor growth dynamics.

Main Results:

• STAT1-/- mice exhibited accelerated spontaneous tumorigenesis.
• CRT/E7 vaccination in STAT1-/- mice resulted in a controlled tumor response.
• Immunological analysis revealed increased circulating CD4+ and CD8+ T cells and tumor-specific cytotoxic T cells.
• Reduced lymphocyte exhaustion and more rapid spontaneous tumor growth were observed in STAT1-/- mice.

Conclusions:

• STAT1 deletion accelerates HPV-driven tumorigenesis.
• STAT1-/- mice maintain immunocompetency, enabling a therapeutic response to CRT/E7 vaccination, characterized by enhanced T cell immunity.