Tumor-infiltrating CCR2⁺ inflammatory monocytes counteract specific immunotherapy

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• The tumor microenvironment (TME) critically influences tumor progression, involving diverse immune cells with varying functions.
• Non-invasive immunization platforms, like DIVA and its optimized version DIVA², offer therapeutic vaccination strategies against tumors.

Purpose of the Study:

• To investigate the therapeutic effects of DIVA² in an MC38 tumor model.
• To elucidate the mechanisms within the TME following DIVA² immunization.

Main Methods:

• Utilized DIVA² transcutaneous immunization in an MC38 tumor model.
• Employed high-dimensional flow cytometry and single-cell mRNA-sequencing to analyze tumor-infiltrating leukocytes.
• Investigated the role of CCR2+ cells through antibody-mediated depletion.

Main Results:

• DIVA² induced transient tumor control mediated by cytotoxic CD8+ T cells.
• An immune evasion phase was observed, characterized by the recruitment of immunosuppressive CCR2+ PDL-1+ monocytes.
• Depletion of CCR2+ cells prolonged survival, identifying these monocytes as key players in tumor immune escape.

Conclusions:

• DIVA² effectively generates antigen-specific T cell responses for therapeutic cancer control.
• Immunosuppressive CCR2+ monocytes in the TME counteract DIVA² efficacy and represent a critical target for enhancing cancer immunotherapy.