IMMUNOLOGY2024™ Conference Recordings-Myeloid cells in cancer: old challenges and new opportunities

Video Transcription

Video Summary

The speaker discusses the challenge of targeting myeloid cells in cancer therapeutically. He explains that despite their diversity, myeloid cells largely exist in a limited number of functional states, including a pathological suppressive state seen in cancer. Because these states are highly redundant and context-dependent, broad myeloid targeting is difficult and potentially harmful.<br /><br />He presents two recent studies. First, in tumors, neutrophils undergo ferroptosis, a lipid-peroxidation-driven form of cell death. Rather than killing tumor cells, ferroptosis in neutrophils converts them into strongly immunosuppressive cells. Blocking ferroptosis reduces this suppressive activity and improves anti-tumor responses, while inducing ferroptosis worsens them. This process occurs selectively in the tumor microenvironment.<br /><br />Second, he describes ATR inhibition with ceralasertib, a DNA damage repair drug. In combination with PD-L1 blockade, intermittent dosing improves anti-tumor immunity and survival. The benefit depends on CD8 T cells and is mediated by type I interferon, which reshapes the microenvironment: it depletes monocytic suppressive cells and macrophages, neutralizes PMN-MDSCs, activates dendritic cells, and increases PD-1 on T cells. The key message is that successful myeloid-targeted therapy likely requires pleiotropic, microenvironment-driven strategies that affect multiple myeloid programs, not a single cell type or pathway.

Keywords

myeloid cells

cancer immunotherapy

ferroptosis

neutrophils

ATR inhibition

type I interferon

PD-L1 blockade