Trends in Molecular Medicine
ReviewPutting the brakes on anticancer therapies: suppression of innate immune pathways by tumor-associated myeloid cells
Section snippets
Tumor microenvironments determine the directions of chemotherapeutic responses
Various intrinsic mechanisms, such as genetic alterations, chromatin modifications, and enrichment of cancer stem/initiating cells, negatively regulate the responses to anticancer therapeutics. Conversely, accumulating evidence has revealed that the interactions of tumor cells with non-transformed cells such as stromal cells, endothelial cells, and inflammatory cells are a determining factor in manipulating tumorigenic activities and tumor responses to anticancer drugs 1, 2, 3. In addition,
Tumor-associated myeloid cells generate chemoresistant niches
The immune system provides both pro- and antitumorigenic effectors in the course of tumor progression. Likewise, tumor microenvironments have a profound impact on the biological behaviors of tumor-infiltrating leukocytes on responses to anticancer agents. In particular, myeloid cells display phenotypic plasticity when encountering different tumor microenvironments. Macrophage polarization is tightly regulated through various transcription factors such as interferon regulatory factor (IRF),
Myeloid cell derived soluble mediators generate chemoresistant niches
Accumulating evidence has revealed that various repertoires of cytokines, chemokines, and growth factors strongly influence tumor progression and resistance to anticancer agents [24]. Indeed, multiple cytokine networks in tumor microenvironments adopt dedicated strategies to evade therapeutic responses to anticancer agents by enhancing tumor cell survival, angiogenesis, matrix remodeling, and repression of host antitumor immunity [25]. These observations underscore the complex regulatory
Damage-associated molecular pattern-mediated innate immune pathways regulate chemoresistant niches
Although the vast majority of cancers arise from de novo oncogenic and epigenetic alterations, most tumors manifest continuous inflammatory signal activation as a result of smoldering inflammation. This occurs even in the absence of infection or autoimmunity and causes tumor progression and resistance to anticancer therapies [2]. In particular, endogenous inflammatory mediators, termed damage-associated molecular patterns (DAMPs), are released mainly from stressed or injured cells and
Myeloid cell phagocytic pathways regulate chemoresistant niches
Phagocytosis serves as a physiological process for the removal of debris produced by dying cells, which might cause inflammation and autoimmunity [60]. In addition, phagocytosis facilitates the processing and presentation of various repertoires of immunogenic antigens to tumor-specific lymphocytes under certain conditions [61]. Phagocytosis is mainly mediated through PRR-dependent recognition of phosphatidylserine (PS) exposed on the surface of apoptotic cells, and recent studies have
Regulation of chemotherapy-induced stress responses by myeloid cells: the mechanistic insight
Several types of chemotherapeutic agents have an intrinsic capacity to trigger ICD in mutated, hyperploid tumor cells, which coordinately programs innate immune systems to efficiently elicit antitumor immune responses. The induction of ICD is associated with the induction of ER stress, the generation of reactive oxygen species (ROS) and the activation of autophagy, leading to the cell surface translocation of CRT and the extracellular release of ATP 59, 69, 72. Moreover, taxol or doxorubicin
Concluding remarks and future perspectives
We provide an overview of myeloid cell mediated regulation of anticancer therapies. Although ICD elicited by anticancer chemotherapy contributes to endogenous antitumor immunosurveillance, several negative regulatory pathways described here blunt the innate immune systems that can be manipulated to trigger antitumor immune responses by ‘non-immunogenic’ anticancer agents. Further elucidation of the role of myeloid cell derived negative regulators would greatly advance our knowledge about
Acknowledgments
We would like to acknowledge Dr Muhammad Baghdadi for graphical assistance. We apologize to the authors whose work could not be cited owing to space limitations. This study is partially supported by Grant-in-Aids for Scientific Research and Scientific Research for Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) and the Ministry of Health, Labor, and Welfare, the Naito Foundation, and the Astellas Foundation for Research on Metabolic Disorders.
Glossary
- Chemoresistant niche
- although cell intrinsic processes play a major role in chemotherapeutic responses, non-transformed cells, such as fibroblasts, myeloid cells, etc., in tumor microenvironments contribute to support tumor cell survival following the administration of chemotherapeutic agents. In this case, coordinated activation of genotoxic stress signals and inflammation specifically triggered by chemotherapy serves as a driving force to activate non-transformed cells, leading to the release
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2017, International Review of Cell and Molecular BiologyCitation Excerpt :BC patients present elevated levels of MDSCs and the highest are found in patients with metastatic disease (Diaz-Montero et al., 2009; see Markowitz et al., 2013 for a review of MDSCs’ role in BC). To make matters worse, a distinct characteristic of MDSCs is that they can induce certain responses to cancer treatments by manipulating negative regulatory factors of the patients’ immune pathways to generate chemoresistant niches (Jinushi et al., 2013). MDSC induction is likely caused by a general inflammatory process in BC (Jiang and Shapiro 2014) and can be associated to a wide variety of cytokines (Gabrilovich et al., 2012).
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2015, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Thus, the antitumor machineries exploited by several immunotherapies and by irradiation might rely on the polarization of tumoricidal macrophages in tumor microenvironments. Some chemotherapeutic agents, such as oxaliplatin and doxorubicin, exploit the process of “immunogenic cell death” (ICD) for tumor cells, leading to the release of inflammatory mediators recognized by pattern-recognition receptors and activating antigen-presenting cells [65,66]. Indeed, clinical responses to anthracyclin and radiotherapy are significantly impaired in patients with advanced breast cancer who possess a loss-of-function allele of TLR-4, as TLR-4 is critical in exploiting ICD-meditated antitumor immunity [67].