The mechanisms of cancer immunoescape and development of overcoming strategies

Abstract

Cancer-induced immunosuppression is a major problem as it reduces the anti-tumor effects of immunotherapies. In cancer tissues, cancer cells, immune cells, and other stromal cells interact and create an immunosuppressive microenvironment through a variety of immunosuppressive factors. Some cancer subpopulations such as cancer cells undergoing epithelial-mesenchymal transition and cancer stem-like cells have immunosuppressive and immunoresistant properties. The production of immunosuppressive factors by cancer cells is mechanistically attributed to oncogenic signals frequently activated in cancer cells, including the STAT3, MAPK, NF-κB, and Wnt/β-catenin signals, which are upstream events leading to immunosuppressive cascades. Moreover, some of these signals are also activated in immunosuppressive immune cells stimulated by cancer-derived factors and contribute to their immunosuppressive activities. Therefore, targeting these signals both in cancer cells and immunosuppressive immune cells may result in the restoration of immunocompetence in cancer patients and improve current immunotherapy.

Natural killer cells as effectors of selection and differentiation of stem cells: Role in resolution of inflammation

“…Fibroblasts from tumor tissues demonstrate an activated phenotype and the ability to secrete many immunosuppressive factors such as TGF, and VEGF (Yaguchi et al, 2011). Our own studies have found that undifferentiated fibroblasts, as well as MSC and CD14 + HLA-DR À monocytes, were significantly more susceptible to NK cellmediated cytotoxicity (Jewett et al, 2010); therefore, these cells may condition NK cells to undergo split anergy and become regulatory NK cells.…”

The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4

“…To enable such combinations, it is critical to determine how targeted therapies affect immune function in the tumor microenvironment and peripheral systems. Immunogenic cell death, characterized by secretion of cell damage-associated hallmark molecules consisting of calreticulin (CRT), HSP70 and 90 proteins, HMGB1, and ATP, increased expression of tumor antigens and HLA molecules, and decreased expression of immunosuppression factors are desirable features for potential immune sensitization (3,4). These effects may allow targeted agents to not only directly inhibit tumor growth, but also further enhance immune response by immunotherapy, through either tumor cell intrinsic or extrinsic immunomodulatory mechanisms, thus making the cancer therapy more effective and durable.…”

Stat3 inhibitor abrogates the expression of PD-1 ligands on lymphoma cell lines

“…12,23,24 Stat3 is also a key molecule for immune suppression by stromal cells such as tumor associated macrophages (TAMs). [23][24][25] Stat3 activation in myeloid cells is significantly related to immune suppression. 26,27 We previously showed that IL-27/Stat3 signals were closely contributed to PD-L1/2 expression in TAMs.…”