Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Abstract

The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity.

Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes

“…As discussed in Part I, the proportions of suppressive cell populations such as MDSCs are increased in large and progressing tumors. Blocking MDSC recruitment to or activity in the TME renders the tumor sensitive to immunotherapy [reviewed in depth elsewhere ( 105 )]. We and others have shown that MDSCs are rapidly recruited to the PDAC TME via multiple chemokine and cytokine axes including CXCR2 ( 8 , 106 , 107 ), GM-CSF ( 108 , 109 ), and G-CSF ( 8 ).…”

CD244+ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

“…That is, it is assumable that PMN-MDSCs would be provided from the local peritoneal cavity and spread systemically. Besides, both G-CSF and IL-6 are known to activate the signaling of signal transducer and activator of transcription 3 (STAT-3), which is strongly associated with the induction of PMN-MDSCs (43). The precise mechanisms of PMN-MDSC induction remain a significant issue that requires further investigation.…”

Transforming growth factor‐beta1 and myeloid‐derived suppressor cells: A cancerous partnership

“…9,110 MDSCs can support cancer progression by enhancing tumor growth, neoangiogenesis, and metastasis, and they are abundant within TME and spleen, and peripheral blood. 111,112 In general, it is accepted that MDSCs support tumor growth and metastasis due to their capacity to protect cancer cells from immune surveillance, facilitate TME reorganization, contribute to pre-metastatic niche formation, and promote cancer-EMT. 13 MDSCs may promote primary tumor progression by both immunological (discussed later) and nonimmunological mechanisms.…”