Myeloid immunosuppression and immune checkpoints in the tumor microenvironment

Abstract

Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages, are critical mediators for sterile and nonsterile inflammation, persistent inflammation, such as that which occurs in cancer, is known to disturb normal myelopoiesis. This disturbance leads to the generation of immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment, immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy. Indeed, various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies. These include antiinflammatory agents, therapeutic blockade of the mobilization and survival of myeloid cells, and immunostimulatory adjuvants. More recently, immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells. In this review, we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

“…It is well known that IL-4R is not only expressed on 4T1 tumor cells but also upon immune cells, specifically myeloid-derived suppressor cells (MDSCs) and tumorassociated macrophages (TAMs). Both of these immune cell populations contribute to immunosuppression within the TME as well as metastasis (25)(26)(27)(28). To investigate whether the observed inhibition of tumor growth was due to direct targeting of IL-4R + tumor cells, to depletion of IL-4R + MDSCs and TAMs, or to a combination of the two, we orthotopically implanted IL-4R + 4T1 cells in an IL-4R knockout mouse strain (IL4Rα -/-) and treated with either PBS or DABIL-4 thrice weekly starting on day 7.…”

Decoding the Role of Interleukin-30 in the Crosstalk between Cancer and Myeloid Cells

“…Activated myeloid cells are the primary cellular source and one of the targets of IL-30, which can also be produced by cancer cells, especially, in aggressive tumors, as observed in the breast and prostate. This review briefly reports on the immunobiology of IL-30 and related cytokines, by comparing mouse and human counterparts, and then focuses on the mechanisms whereby IL-30 amplifies intratumoral myeloid cell infiltrate and triggers a vicious cycle that worsens immunosuppression in the tumor microenvironment (TME) and constitutes a real threat for a successful immunotherapeutic strategy.Cells 2020, 9, 615 2 of 14 of reactive oxygen species (ROS), nitric oxide (NO), and ectoenzymes, which regulate the adenosine metabolism; expression of immune checkpoint molecules [10,11]; depletion of metabolites critical for lymphocyte functions [12,13]; and through their secretion of growth, angio-lymph-angiogenic factors and inflammatory mediators [13], that are crucial for tissue remodeling and tumor development.Recent insights into this inflammatory milieu, specifically in breast (BC) and prostate (PC) cancers, have unveiled a role for the novel immunoregulatory mediator Interleukin(IL)-30/IL-27p28 [14] in the TME and in the intricate relationship between cancer and myeloid cells, which orchestrates tumor-promoting events with evident clinical implications [15,16].…”

“…Cells 2020, 9, 615 2 of 14 of reactive oxygen species (ROS), nitric oxide (NO), and ectoenzymes, which regulate the adenosine metabolism; expression of immune checkpoint molecules [10,11]; depletion of metabolites critical for lymphocyte functions [12,13]; and through their secretion of growth, angio-lymph-angiogenic factors and inflammatory mediators [13], that are crucial for tissue remodeling and tumor development.…”

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

“…Since then, ICBs targeting other immune-checkpoints (e.g., TIM3, LAG3, VISTA) have entered several clinical trials [258]. ICBs have indeed markedly improved cancer patients' outcomes, but several patients still fail to sufficiently respond to these immunotherapies [259]. To overcome this problem, combination of ICBs with existing conventional anticancer therapy are being extensively studied in both clinical as well as pre-clinical studies.…”