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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite the initial enthusiasm, IFN-γ did not demonstrate efficacy in oncology patients and its FDA approvals are only for non-oncologic indications. Proposed reasons for this lack of efficacy include activation of Myeloid-Derived Suppressor Cells (MDSC) and a narrow therapeutic index.
Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Published in Gabriel Virella, Medical Immunology, 2019
Scott Sugden, Damien Montamat-Sicotte, Karen K. Yam, Joseph Murphy, Bader Yassine Diab, Virginia Litwin
HSCs give rise to the common myeloid progenitors (CMPs), which in turn give rise to the monocyte/dendritic cell progenitors (MDPs) or the granulocyte/monocyte progenitors (GMPs). Maturation then occurs in three stages: monoblast, promonocyte, and monocyte. Monoblasts expressing CD64, CD33, HLA-DR, CD34, and CD4 are derived from both MDP and GMP. As differentiation progresses transition toward promonocytes, there is a loss of CD34 expression and increased expression of CD4 (Figure 10.2). Changes in the expression levels of CD34, HLA-DR, CD117/c-kit, CD64, CD45, CD36, CD14, and CD300 are used to delineate monocyte maturation stages (Table 10.1). Monocytic-myeloid-derived suppressor cells (M-MDSCs) are also differentiated from MDPs.
Tumor Microenvironment, Therapeutic Resistance, and Personalized Medicine
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
In healthy individuals, an intact immune system functionally mounts antitumor responses, but mechanisms of immune suppression under pathological conditions can prevent this process and promote disease progression. Both positive and negative checkpoint signals are involved in T-cell activation as host response to prevent damage and minimize autoimmunity. Cytotoxic T cells in the TME are activated through continuous engagement of inhibitory cell surface receptors, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) receptor, through ligand overexpression [30]. Alternatively, antitumor T cell responses are suppressed within an immunosuppressive milieu, as tumorigenesis induces expansion of a myeloid-derived suppressor cell (MDSC) population that comprises early myeloid progenitors, immature dendritic cells (DCs), neutrophils, and monocytes, a process that implicates endocrine communication with the immune system through enhanced secretion of chemokines, including granulocyte–macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) [31, 32]. Tumor-induced recruitment of immunosuppressive myeloid lineages not only diminishes adaptive immunity, but fosters angiogenesis through production of basic fibroblast growth factor (bFGF), TGF-β and VEGFA [33]. MDSCs also inhibit effector T-cell proliferation, activation, and migration, while enhancing immunosuppressive regulatory T-cell expansion [34].
Role of the BMP6 protein in breast cancer and other types of cancer
Published in Growth Factors, 2021
Andrea Marlene García Muro, Azaria García Ruvalcaba, Lourdes del Carmen Rizo de la Torre, Josefina Yoaly Sánchez López
The appearance of myeloid-derived suppressor cells (MDSC) is associated with metastatic disease and poor prognosis. MDSCs are immature myeloid cells that suppress the antitumor immune response and facilitate metastasis, mainly by inhibiting the activation and proliferation of T cells by releasing reactive oxygen species and arginase-1, which function as immunosuppressive factors, but also through immunodependent mechanisms such as improvement of angiogenesis, degradation of the extracellular matrix and formation of the premetastatic niche. Contrary to MDSC, increment of T lymphocytes indicates an antitumor response and a better prognosis (Cao et al. 2014).
Neoantigen vaccine platforms in clinical development: understanding the future of personalized immunotherapy
Published in Expert Opinion on Investigational Drugs, 2021
Suangson Supabphol, Lijin Li, S. Peter Goedegebuure, William E. Gillanders
Neoantigen vaccine therapy appears to be extremely well tolerated with minimal side effects and/or adverse events. As such, neoantigen vaccines can be used alone (for example in the adjuvant setting), or can be readily combined with other treatments. Based on mechanism of action, it is likely that neoantigen vaccines will be particularly effective in combination with cancer immunotherapies [85–88]. The tumor microenvironment is rarely hospitable to tumor-specific T cells. It is likely that cancer immunotherapies designed to abrogate immune checkpoint pathways and/or target the immunosuppressive tumor microenvironment will be particularly effective. Early stage clinical trials are ongoing combining neoantigen vaccines and immune checkpoint inhibitors. Targeting CTLA4 may facilitate neoantigen-specific T cell priming, while targeting PD-1/L1 may prevent exhaustion once T cells arrive in the tumor. Strategies targeting tumor associated macrophages, and/or myeloid-derived suppressor cells are also likely to be important.
Association of TRF2 expression and myeloid-derived suppressor cells infiltration with clinical outcome of patients with cutaneous melanoma
Published in OncoImmunology, 2021
Marius Ilié, Elisabeth Lantéri, Emmanuel Chamorey, Brice Thamphya, Marame Hamila, Henri Montaudié, Alexandra Picard-Gauci, Sophie Gardrat, Thierry Passeron, Sandra Lassalle, Elodie Long-Mira, Julien Cherfils-Vicini, Eric Gilson, Véronique Hofman, Paul Hofman
An efficient antitumor immune response is of vital importance in preventing cancer progression and metastasis, as well as in successful chemotherapy or immunotherapy.22 Among the immunosuppressive properties of tumors, the recruitment and activation of myeloid-derived suppressor cells (MDSCs) facilitate cancer progression.23 A recent study demonstrated that cancer cells recruited and directly activated MDSCs in a TRF2-dependent manner, dampening NK and CD8 + T cell cytotoxicity.18 Moreover, patients with several types of carcinomas (including, breast, gastric, ovarian, and lung) with high TRF2 expression also exhibited marked MDSCs infiltration and reduced overall survival.18 CD11b and CD33 are mainly used as markers for human MDSCs.24 However, these markers are expressed by cells of the myelocytic lineage and by NK cells, so they are not specific enough to identify human neutrophils.25,26 Instead, neutrophils (or G-MDSCs) are found to be CD14 low and CD15 high, whereas the monocytes (or Mo-MDSCs) are CD14 high and CD15 low.27 Some studies showed that patients with melanoma have significantly high levels of blood circulating CD33+ CD11b+CD15 + G-MDSCs with immune suppressive phenotype, while low levels of G-MDSCs before anti-CTLA-4 therapy could correlate with an objective clinical response, long-term survival, and an improved clinical status.28–30