Type I Interferon Modulates the Function of Ly6C High-Expressing Naïve CD8⁺ T Cells to Promote an Antitumor Response

Background: Ly6C expression in naïve CD8+ T cells plays a crucial role in enhancing their effector activity, suggesting potential implications for cancer immunotherapy. This study investigates the functional impact of Ly6C expression on CD8⁺ T cells and explores albumin-conjugated IFNβ (Alb-IFNβ) as a strategy to modulate Ly6C expression and improve cancer vaccine efficacy. Methods: We analyzed the functional differences between Ly6C high-expressing (Ly6C^hi) and Ly6C low-expressing (Ly6C^lo) naïve CD8⁺ T cells in tumor suppression. To assess the role of type I interferon signaling, we administered Alb-IFNβ in C57BL/6J and IFNAR^-/- mice and measured Ly6C expression in CD8⁺ T cells. The therapeutic potential of Alb-IFNβ was further evaluated in combination with a vaccinia virus encoding the HPV-16 E7 antigen (CRT-E7 vaccine) in a syngeneic TC-1 tumor model, assessing tumor growth, survival, and antigen-specific CD8⁺ T cell responses. Results: Naïve CD8⁺ T cells with elevated Ly6C expression exhibited enhanced tumor-suppressive capacity and required lower activation thresholds for effector function. Alb-IFNβ treatment selectively increased Ly6Chi naïve CD8⁺ T cells in C57BL/6J mice but not in IFNAR^-/- mice, confirming type I interferon's role in Ly6C regulation. Combining Alb-IFNβ pretreatment with the CRT-E7 vaccine significantly enhanced antigen-specific CD8⁺ T cell immunity, reducing tumor growth and prolonging survival in TC-1 tumor-bearing mice. Conclusions: Our findings suggest that Alb-IFNβ may enhance the antitumor activity of naïve CD8⁺ T cells by modulating Ly6C expression. Alb-IFNβ could potentially improve the efficacy of HPV vaccinia-based cancer vaccines, warranting further investigation as an adjuvant strategy in cancer immunotherapy.