Abstract
Transformation and growth of tumor cells are associated with profound alterations in neighbouring cells and their environment, together forming the tumor microenvironment (TME). The TME provides a conducive but complex milieu for the tumors to thrive while incapacitating the immune cells that home there as part of our natural immunosurveillance mechanism. The orchestration of this successful survival strategy by tumor cells is associated with exploitation of numerous metabolic and immune checkpoints, as well as metabolic reprogramming in the tumor cells. Together these form an intricate network of feedback mechanisms that favor the growing tumor. In addition, an ecosystem of microbiota, proximal or distal to tumors, influences the successful survival or elimination of tumor cells mediated by immune cells. Discovery and clinical application of immune checkpoint inhibitors (ICIs) i.e., monoclonal antibodies (mAbs) blocking specific immune checkpoints CTLA-4 and PD-1/PD-L1, have revolutionized therapy of various cancers. However, they are still associated with limited response rates, severe immune-related adverse events, development of resistance, and more serious exacerbation of cancer progression termed hyper-progressive disease. Checkpoint inhibitors only represent a milestone and not the finish-line in the quest for treating and curing cancer. Efforts are underway to investigate and develop inhibitors of other immune as well as metabolic checkpoint molecules. Future therapy for various cancers is projected to target immune and metabolic checkpoints and the microbiota together.
Highlights
This review will provide a brief overview of the emerging concepts of immune and metabolic checkpoints, the tumor microenvironment and gut microbiota, and how they may be targeted clinically to achieve new milestones in cancer therapy
It has been shown that B7-H3 (a putative immune checkpoint expressed on tumor cells and antigen presenting cells (APCs) in tumor microenvironment (TME)) plays an important role in regulating cancer cell metabolism, increases hypoxia-induced factor-1α (HIF-1α) activity, glucose uptake, glycolysis and lactate production in breast cancer cells [44]
The idea of killing and eliminating tumors by mobilizing the host’s own immune system has been around for more than half a century, initially brought forward as active specific immunotherapy (ASI) for cancers, which resulted in clinical testing of numerous therapeutic cancer vaccines
Summary
Cancer is among one of the leading causes of death worldwide with ~ 18 million new cases and ~ 9.5 million deaths in the year 2018 alone [1].
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