Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity

Abstract

Our current understanding of human tumor-resident myeloid cells is, for the most part, based on a large body of work in murine models or studies enumerating myeloid cells in patient tumor samples using immunohistochemistry (IHC). This has led to the establishment of the theory that, by and large, tumor-resident myeloid cells are either “protumor” M2 macrophages or myeloid-derived suppressor cells (MDSC). This concept has accelerated our understanding of myeloid cells in tumor progression and enabled the elucidation of many key regulatory mechanisms involved in cell recruitment, polarization, and activation. On the other hand, this paradigm does not embrace the complexity of the tumor-resident myeloid cell phenotype (IHC can only measure 1 or 2 markers per sample) and their possible divergent function in the hostile tumor microenvironment. Here, we examine the criteria that define human tumor-infiltrating myeloid cell subsets and provide a comprehensive and critical review of human myeloid cell nomenclature in cancer. We also highlight new evidence characterizing their contribution to cancer pathogenesis based on evidence derived from clinical studies drawing comparisons with murine studies where necessary. We then review the mechanisms in which myeloid cells are regulated by tumors in humans and how these are being targeted therapeutically.

The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

“…Importantly, however, the intratumoral Tie2 + macrophages were reduced in both animal models tested (Figures 3C and 3H), indicating that rebastinib affects the dynamics of specific macrophage subpopulations in the primary tumor microenvironment in a context-dependent manner, thus without necessarily affecting the total macrophage population, as also evidenced by radiotherapy, chemotherapy or other drug treatments (24,27,64,65). In addition, in PyMT tumors, although TMEM density was not decreased by rebastinib, TMEM function was dramatically impaired by rebastinib effects on Tie2 + macrophages, as evidenced by decreased vascular permeability, circulating tumor cells, and metastasis in vivo and decreased TMEM-associated transendothelial migration in vitro .…”

Circulating neutrophil subsets in advanced lung cancer patients exhibit unique immune signature and relate to prognosis

“…49,50 One of the current challenges in the field of myeloid cells in cancer is the phenotypic characterization and cancer-driven modulations these cells in general, and neutrophils in particular, undergo in cancer. 51,52 Since the first documentations of the presence of LDN within the classical "PBMC fraction" following density gradient, [18][19][20] few specific markers have been suggested to characterize cancer-related neutrophils, including the distinction between LDN and HDN, as well as mature vs immature neutrophils. Singhal et al proposed a combination of CD15, CD16, and CD10 to segregate between mature (segmented) neutrophils, immature (band) neutrophils, and earlier myelocyte stages, 38 whereas Lang et al proposed a combination of CD66b, CD11b, and CD16 markers.…”

A Listeria-Derived Polypeptide Promotes In Vivo Activation of NK Cells for Antitumor Therapy

“…The ability to promote NK cell activation appears to benefit Lm because IFNγ secreting NK cells responding to p60/L1S rapidly switch to secretion of IL-10 (21). IL-10 has been argued both to promote anti-tumor resistance in the B16.F10 model (32), and to promote growth of B16.F10 melanoma cells (34). However, given our finding that IFNγ is important for the observed anti-tumor effects, we did not further explore NK cell IL-10 production in the present work.…”