High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

Abstract

A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells are located. Regardless of the fact that large numbers of tumor-specific T cells can be generated in patients by active immunization or adoptive transfer, these T cells do not readily translate to tumor cell killing in vivo. The immune regulatory mechanism which prevents autoimmunity may be harnessed by tumor cells for the evasion of immune destruction. Regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert to cause the subversion of anti-tumor immunity in the tumor microenvironment. This redundant immunosuppressive network may pose an impediment to efficacious immunotherapy, thus facilitating tumor progression. Cancer progression clearly documents the failure of immune control over relentless growth of tumor cells. Detailed knowledge of each of these factors responsible for creating an immunosuppressive shield to protect tumor cells from immune destruction is essential for the development of novel immune based therapeutic interventions of cancer. Multi-pronged targeted depletion of these suppressor cells may restore production of granzyme B by CD8+ T cells and increase the number of IFN-γ producing CD4+ T cells.

Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment

“…However, CD8 + cytotoxic T cells (CTL) are thought to be primarily responsible for mediating antitumor immunity, while CD4 + T cells provide help to antigen presenting cells, promoting complete licensing of CD8 + T cell activation (28,29). Given this key role, there has been a large interest in mechanisms of tumor immune evasion from CD8 + T cells (30,31). Thus, to evaluate the impact of PC-TAS interactions on CD8 + T cell-mediated cytotoxicity, MART-1 tumor antigen-specific CD8 + T cells were employed in a classical CTL assay (20).…”

Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy

“…[23][24][25] Importantly, a variety of cells in the TME, including both specific-and nonspecificinduced Tregs, M2 macrophages, myeloidderived suppressor cells, tumour cells and associated fibroblasts can also limit and block specific T cells' function, thereby contributing to persistence of the neoplasia. 26…”

Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum album L. therapy in patients with advanced or metastatic cancer

“…Cancer cells are able to gain control over a number of inhibitory pathways that are important for controlling immune responses [1,2]. By overexpressing programmed cell death protein ligands (PD-Ls) that bind to the immune checkpoint receptor programmed cell death protein 1 (PD-1), solid tumour cells can modulate T-cell activation in inflammatory cascades.…”