Tumor-associated monocytes and neutrophils: Targets for immunotherapy?

 Our goal is to better understand the immune microenvironment in cancers using advanced methodologies, including in vivo imaging and single-cell genomics. In particular, we aim to unveil the immense potential of myeloid populations in cancers, an emerging field. Real-time intravital multi-photon microscopy provides insight into dynamic cell migration and intercellular communication. We reveal the heterogeneity of myeloid cells through single-cell RNA sequencing in both pre-clinical and clinical specimens. This approach provides novel avenues for immunotherapy of cancers by identifying promising targets in tumor immunity.

Specifically, we have uncovered an immunosuppressive role for non-classical monocytes that mediate resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following VEGF signaling blockade, resulting in the recruitment of CX3CR1+ monocytes into the tumor. Intravital microscopy revealed that CX3CR1 is critical for monocyte transmigration across the endothelium in tumors. Moreover, these monocytes recruit neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Neutrophils are key players in this immunosuppressive environment, contributing to tumor progression and resistance to therapy. The recruited neutrophils interact with the tumor microenvironment to suppress the anti-tumor immune response, further aiding in the tumor’s evasion of the immune system.

Taken together, we identified immunosuppressive monocytes and neutrophils as key players in tumor resistance to conventional therapies in cancers. We also revealed molecular mechanisms underlying treatment resistance, suggesting potential immunomodulatory strategies to enhance long-term clinical outcomes.