Avoiding Immune Destruction

While the previous hallmark of cancer was related to the stimulatory effect of the inflammatory process on tumor growth, the avoiding of immune destruction represents a mechanism that substantially limits the effectiveness of the mechanisms responsible for the recognition and removal of tumor cells by the immune system. There are, however, several mechanisms that allow the tumor to evade immune destruction. One of the most important is immune suppression in the tumor microenvironment, which is mediated by CD4+ CD25+ FoxP3+ regulatory T (Tregs) cells as well as other suppressive cells, that are attracted to the tumor microenvironment by chemokines produced by tumor cells. Myeloid-derived suppressor cells (MDSCs), which are capable of markedly suppressing T-cell responses, are also significantly involved in immunosuppressive effects in the tumor microenvironment. Another mechanism allowing the evasion of immune destruction includes disruption of antigen presentation. This phenomenon is a consequence of down-modulating processes associated with antigen processing, which impairs the efficiency of the major histocompatibility complex (MHC) I pathway, proteosome subunits latent membrane protein (LMP)2 and LMP7, transporter associated with antigen processing (TAP) protein, and tapasin. As a result, the expression of tumor antigens is significantly suppressed, resulting in an increased incidence of tumors as well as metastasis, as cytotoxic T lymphocytes are unable to recognize the corresponding antigens on tumor cells. Tumors may also evade immune destruction by tumor as well as nontumor cells in the tumor microenvironment producing immune-suppressive mediators such as TGF-β, VEGF, and IL-10. Other factors limiting the destruction of tumor cells by the immune system include tolerance and immune deviation, which result from tumor cells not expressing costimulatory molecules, thereby inducing anergy or tolerance to T cells. Tumors can also induce immune deviation by shifting the balance from Th1 to Th2. In addition, tumor cells may express inhibitory molecules such as programmed cell death (PD)-L1/B7H1 and, conversely, downregulation of death receptors may occur. Finally, tumor cells may also evade tumor destruction by elimination of tumor-specific cytotoxic lymphocytes (CTLs) via induction of apoptosis (Vinay et al. 2015; Zhao et al. 2021).