Abstract
Cancer development is dependent on intrinsic cellular changes as well as inflammatory factors in the tumor macro and microenvironment. The inflammatory milieu nourishes the tumor and contributes to cancer progression. Numerous studies, including ours, have demonstrated that the tumor microenvironment is immunosuppressive, impairing the anticancer immune responses. Chronic inflammation was identified as the key process responsible for this immunosuppression via induction of immature myeloid-derived suppressor cells (MDSCs). Upon a prolonged immune response, MDSCs are polarized toward immunosuppressive cells meant to control the exacerbated immune response. In cancer, the chronic inflammatory response renders the MDSCs harmful. Polarized MDSCs suppress T-cells and natural killer cells, as well as antigen-presenting cells, abrogating the beneficial immune response. These changes in the immunological milieu could also lead to high frequency of mutations, enhanced cancer cell stemness, and angiogenesis, directly supporting tumor initiation, growth, and spreading. The presence of MDSCs in cancer poses a serious obstacle in a variety of immune-based therapies, which rely on the stimulation of antitumor immune responses. Cumulative data, including our own, suggest that the selection of an appropriate and effective anticancer therapy must take into consideration the host’s immune status as well as tumor-related parameters. Merging biomarkers for immune monitoring into the traditional patient’s categorization and follow-up can provide new predictive and diagnostic tools to the clinical practice. Chronic inflammation and MDSCs could serve as novel targets for therapeutic interventions, which can be combined with conventional cancer treatments such as chemotherapy, radiotherapy, and cancer cell-targeted and immune-based therapies. Intervention in environmental and tumor-specific inflammatory mechanisms will allow better clinical management of cancer toward more efficient treatment.
Highlights
While some cancers are triggered by intrinsic cellular changes such as germ-line mutations, the majority of tumors are caused by acquired somatic mutations due to alterations in homeostatic environmental factors
We have recently shown that TNF-α plays a critical role in myeloid-derived suppressor cells (MDSCs) accumulation and suppressive function as it leads to myeloid cell differentiation arrest, which is accompanied by a specific polarization of these cells toward an immunosuppressive phenotype, inducing dysfunction of effector immune cells [18]
The cumulative data depicting the capacity of effector and regulatory immune cells to shape the environment toward supporting tumor growth highlight the critical role of chronic inflammation and associated immunosuppression, mediated by MDSCs, as a major obstacle in the success of chemo- and immune-based anticancer therapies
Summary
While some cancers are triggered by intrinsic cellular changes such as germ-line mutations, the majority of tumors are caused by acquired somatic mutations due to alterations in homeostatic environmental factors. The common denominator of these processes is chronic inflammation, which is an abnormal and sustained form of a protective response. It starts as an acute inflammation; a beneficial response resolving insults such as newly encountered pathogens or transformed cells. The prolonged response leads to loss of tissue homeostasis, resulting in a condition similar to unhealed wounds [1]. This type of dysregulated responses occur at higher rates in cases of cancer, where transformed cells in conjunction with proinflammatory cells and factors result in tumor development and progression [2]. We highlight the regulatory checkpoints controlled by immunosuppressive cells and factors in the tumor micro and macro environments, focusing on MDSCs: immunosuppressive cells which play a critical role in maintaining normal homeostasis and when polarized under chronic inflammatory conditions could skew the environment toward supporting tumor development and spreading
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