Engineered oncolytic virus armed with anti-PCSK9 scFv boosts long-term CD8⁺ T cell immunity via rewiring MHC-I...

Area of Science:

• Oncolytic virotherapy
• Immunooncology
• Cancer immunology

Background:

• Oncolytic viruses (OVs) show promise for cancer treatment by directly lysing tumor cells and stimulating immune responses.
• The precise immune mechanisms by which OVs exert their effects, particularly concerning T cell responses, are not fully elucidated.
• Understanding these mechanisms is crucial for optimizing OV-based cancer therapies.

Purpose of the Study:

• To investigate the immune consequences of oncolytic virus (VSVΔ51) treatment in colorectal cancer.
• To elucidate the role of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) in the immunosuppressive effects of VSVΔ51.
• To evaluate the therapeutic potential of combining VSVΔ51 with PCSK9 inhibition for enhanced anti-tumor immunity.

Main Methods:

• Treatment of colorectal cancer models with oncolytic VSVΔ51.
• Analysis of T cell receptor signaling in tumor-infiltrating T cells.
• Measurement of PCSK9 secretion and its effect on Major Histocompatibility Complex (MHC)-I expression in cancer cells.
• Combination therapy studies involving VSVΔ51 and PCSK9 inhibitors.
• Development and testing of engineered VSVΔ51 expressing anti-PCSK9 single-chain variable fragments.
• Assessment of CD8+ T cell memory and efficacy of anti-PD-1 therapy.

Main Results:

• VSVΔ51 treatment was found to suppress T cell receptor signaling in tumor-infiltrating T cells.
• VSVΔ51-infected cells upregulate PCSK9 secretion, leading to lysosomal degradation of MHC-I on bystander cells.
• Inhibition of PCSK9 synergized with VSVΔ51 to reduce tumor growth and achieve complete regression in microsatellite-stable (MSS) colorectal cancer models.
• The combination therapy promoted the development of stem-like CD8+ T cells and established durable anti-tumor memory.
• Engineered VSVΔ51 expressing anti-PCSK9 enhanced viral replication, sustained T cell memory, and improved anti-PD-1 therapy efficacy.

Conclusions:

• PCSK9 plays a significant role in the immunosuppressive feedback loop following oncolytic viral infection.
• Combining oncolytic virotherapy with PCSK9 inhibition represents a promising strategy to overcome immune suppression and enhance anti-tumor responses.
• Engineered oncolytic viruses targeting PCSK9 offer a potential advancement in cancer immunotherapy, particularly for microsatellite-stable tumors.