In recent years, major discoveries in the field of tumor immunology have revolutionized cancer treatment and are now offering significantly improved outcomes for patients with advanced disease. While highly efficacious in some patients, immune checkpoint blocking therapies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1), lead to only modest or minimal responses in the majority of cases. Several reasons have been suggested to contribute to the varied efficacy of current immunotherapies, including the lack of tumor-reactive T cells as well as the impaired ability of these cells to infiltrate tumors. The strong interest in directly targeting T cells has led to reduced emphasis on the importance of innate immune cells, such as myeloid cells, in controlling the fate of re-activated T cells. In fact, in addition to their fundamental role as the first line of defense against invading pathogens, myeloid cells lie at the forefront of initiating adaptive immune responses by priming and cross-presenting antigens to T cells. Moreover, they modulate the tumor microenvironment by producing factors that (i) promote immune tolerance; (ii) promote angiogenesis; (iii) enhance dissemination of tumor cells and (iv) induce cell survival against anti-tumor therapies. Therefore, controlled regulation of the presence and the composition of myeloid cells within tumors is an important avenue to explore in order to develop efficacious therapies against cancer.

Recent approaches that have been developed to target myeloid cells in the tumor microenvironment include 1) depletion 2) stimulation 3) inhibition of trafficking, and 4) reprogramming of their phenotype, in order to modulate anti-tumor immune responses. Various stimulating agents, such as agonistic anti-CD40 or inhibitory anti-CD47 antibodies, as well as, Toll-like receptor ligands are under clinical development in order to activate immune-based tumor recognition and pro-inflammatory responses of myeloid cells. Additionally, reprogramming of macrophages by a selective class IIa histone deacetylase (HDAC) inhibitor or with a PI3Kγ inhibitor has been shown to have potential benefits in improving current immunotherapy in mouse models. To date, strategies under clinical development that target macrophages mostly involve targeted inhibition of colony-stimulating factor 1 receptor (CSF1R) in order to deplete macrophage populations in tumors. However, therapeutic resistance to these approaches has also been reported. Furthermore, dendritic cell-based cancer immunotherapies have been used in clinical trials for several decades with disappointingly low clinical response rates, rarely exceeding 15%. This can be largely attributed to the lack of our understanding in the underlying pathways and cell types that influence the efficacy and/or response rate of a given treatment. Therefore, (i) understanding the heterogeneity and regulation of the immune cell composition of tumors, and (ii) defining patient cohorts that will respond effectively to a given immunotherapy is likely to dramatically improve current clinical trial design and future drug development.

This Research Topic aims to highlight the significance of monocytes, macrophages, dendritic cells and neutrophils in orchestrating tumor-stroma and stromal-stroma interactions in the tumor microenvironment. We welcome the submission of Original Research, Reviews, Mini-Reviews, Opinion and Perspective articles that cover the recent advances made in understanding the role and targeting of myeloid cells in the tumor microenvironment which includes, but are not limited to the following sub-topics:

1. Heterogeneity of myeloid cells in tumors.
2. Mechanisms regulating myeloid cell functions and trafficking in tumors.
3. Novel approaches to target myeloid cells in the tumor microenvironment.
4. Effective combination treatments utilizing myeloid cells to combat cancer.
5. Resistance mechanisms to cancer therapies driven by myeloid cells.
6. Biomarkers of myeloid cell-induced immunosuppression in cancer.
7. System approaches for modeling immune cell interactions in tumors.
8. Multicellular 3D in vitro models to explore immune and cancer cell interactions.

Submit your idea

Impact

Frontiers in Immunology

Participating Journals

Impact