Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer

Area of Science:

• Oncology
• Immunology
• Virology

Background:

• Microsatellite stable colorectal cancer (MSS CRC) is largely resistant to current immunotherapies.
• Oncolytic viruses are being explored to overcome treatment resistance.

Purpose of the Study:

• To investigate the efficacy of oncolytic reovirus in combination with immune checkpoint inhibition (anti-PD-1) for MSS CRC.
• To elucidate the immunological mechanisms underlying the combination therapy's effects.

Main Methods:

• In vitro and in vivo studies using MSS CRC models (CT26) and microsatellite unstable models (MC38).
• Treatment with oncolytic reovirus and/or anti-PD-1 antibody.
• Analysis of tumor growth, cell death, apoptosis, immune cell infiltration, and molecular pathways (microarray/computational analysis).

Main Results:

• Reovirus plus anti-PD-1 treatment increased cell death in MSS CRC cells ex vivo.
• Combination therapy reduced tumor growth, proliferation, and increased apoptosis in CT26 (MSS) models, but not MC38 (MSI) models.
• The treatment activated innate immunity, antigen presentation, and modulated the tumor microenvironment by reducing immunosuppressive cells and T cell exhaustion.

Conclusions:

• Oncolytic reovirus can sensitize MSS CRC to anti-PD-1 therapy.
• The combination therapy exerts its effects through modulation of immune responses and the tumor microenvironment.
• This approach holds potential for treating immunotherapy-resistant MSS CRC.