Myeloid Cells Hold Promise as Cancer Immunotherapy Targets, Review Says

Immunotherapy has changed the cancer treatment landscape significantly in recent years, with a small but significant portion of patients experiencing deep responses to treatment. A review published in Journal of Hematology & Oncology highlights tumor-resident myeloid cells as targets that may increase the efficacy of immunotherapy in nonresponders.

Myeloid cells are innate immune cells, and they include macrophages, dendritic cells (DCs), neutrophils, monocytes, and myeloid-derived suppressor cells (MDSCs) imprinted by the tumor microenvironment (TME). They each have distinct roles, but generally serve as the first line of defense against pathogens and help repair tissue once pathogens are eradicated—except when commandeered by tumor cells to aid tumor growth. Myeloid cells are complex with significant heterogeneity, making them a challenge to target with immunotherapy and effectively harness for cancer treatment.

“Despite over 40% of cancer patients being eligible to receive immunotherapy, only 12% of patients gain benefit,” the authors wrote. “A key to understanding what differentiates treatment response from nonresponse is better defining the role of the innate immune system in antitumor immunity and immune tolerance.”

The review highlights current strategies for myeloid cell targeting and ongoing trials of novel agents targeting myeloid cells for cancer treatment, including data from the 2021 China Cancer Immunotherapy Workshop in Beijing, an international meeting that included discussions of myeloid cell heterogeneity and function in the TME.

Current strategies targeting myeloid cells in various stages of research and trials highlighted in the review include the following:

• Altering myeloid cell differentiation, proliferation, and recruitment in the TME
• Functionally blocking immune-suppressive myeloid cells
• Reprogramming myeloid cells to acquire pro-inflammatory properties via polarization, metabolic, or epigenetic modification
• Modulating myeloid cells via various cytokines
• Directly targeting myeloid cells via methods such as vaccination or engineered chimeric antigen receptor macrophages (CAR-M)

The majority of therapies using the above methods are still in clinical trial phases, with all but polarization reaching phase 3 trials as of the review. The authors also highlight CAR-Ms as a mechanism they believe may overshadow CAR T cells—a current focus of immunotherapy—in the future. Understanding the various myeloid components and their impacts on the TME is crucial to maximizing the likelihood of therapy response, the authors note.

Emerging targets for myeloid cell manipulation include Siglec-15, a sialic acid; triggering receptor expressed on myeloid cells 2 (TREM2); macrophage receptor with collagenous structure (MARCO); leukocyte immunoglobulin-like receptor B2 (LILRB2); and common lymphatic endothelial and vascular endothelial receptor 1 (CLEVER-1).

Although utilizing multiple agents targeting different myeloid components in tandem with immune checkpoint inhibitors or chemotherapy is the most promising approach, toxicity is an important aspect to consider as these strategies are designed and tested.

“Key areas of continued research include further investigation into the cross talk among cancer cells, myeloid cells, adaptive immune cells, and surrounding cells, like epithelial cells and fibroblasts, to create tolerogenic environments, with the help of single-cell multi-omics technologies,” the authors concluded. Overall, they are optimistic that the immunotherapy landscape will continue to expand and benefit more patients as the intricacies of non–T-cell-based immunotherapy are better understood.

Reference

Wang Y, Johnson KCC, Gatti-Mays ME, Li Z. Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy. J Hematol Oncol. Published online August 28, 2022. doi:10.1186/s13045-022-01335-y