Abstract
The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.
Highlights
The immune system is a complex and dynamic system that operates through an intricate network of cellular interactions and transient functional states
myeloid-derived suppressor cells (MDSC) within the bone marrow are recruited to the peripheral lymphoid organs and the tumour site by growth factors secreted by cancer cells; this, in turn, promotes tumourigenesis via different mechanisms by: permitting immunoevasion by inducing NK cell and T-cell anergy; remodelling the tumour microenvironment (TME) to promote tumour growth; creating and establishing a metastatic niche for cancer dissemination; inducing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) transition to facilitate tumour progression and metastasis; promoting angiogenesis; and improving tumour cell survival through their immunosuppressive activities [60,61,62,63,64,65]
It is unsurprising that the phenotypic heterogeneity in the MDSC population had led to ambiguity in their description and characterisation between investigators, an issue that is compounded by a lack of specific markers in both mouse and human MDSCs [54,67]
Summary
The immune system is a complex and dynamic system that operates through an intricate network of cellular interactions and transient functional states It is involved in various biological activities and is the sine qua non for natural defense of the human body against pathological processes. The immune system plays a pivotal role where immune cells infiltrate tumours, co-evolving and cooperating with cancer cells to create an inflammatory and immunosuppressive microenvironment to facilitate tumour growth and dissemination. Tumour cells can hijack mechanisms that confer survival advantages by increasing proliferation and/or reducing apoptosis [2]. This paradigm of cancer “immunoediting” describes the evolution and selection of cancer cells to develop clinically relevant tumours. We discuss the synergistic treatments of combining immune checkpoint inhibitors with MDSC targeting
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