It is generally acknowledged that cancer cells use three major molecular schemes to minimize the chance for them to be recognized by host immune cells.
- Cancer cells decrease expression levels of class I classical human leukocyte antigens consisting of HLA-A, HLA-B, and HLA-C. These are the equivalents of class I MHC (major histocompatibility complex) or MHC-I, known to be indispensable in mediating antigen presentation by antigen presentation cells (APC) to inactive cytotoxic T lymphocytes, also called Killer T cells. Without adequate expression levels of MHC-I, antigenic peptide processes by APC would not be recognized by the T cell receptor (TCR). In the absence of this crucial primary signaling, Killer T cell activation would be impossible. Hence, the first trick cancer cells employ serves to keep Killer T cells at bay.
- A second scheme is to disable the second major type of host immune cells that are capable of eliminating cancer cells. The immune cell type is Natural Killer (NK) cells. Although always on alert, NK must recognize and winnow out “unwanted” cells, including infected cells and cancer cells. Effective NK recognition depends on a biomarker protein on the surface of unwanted cells. These are Class I non-classical HLA consisting of HLA-E, HLA-F, and HLA-G. The absence of these three biomarkers indicates to NK that the target is found and action needs to be taken. Not surprisingly, cancer cells engage in molecular maneuvering to elevate the expression levels of those HLA gene products, thereby tricking NK cells into letting them go.
- A third trick cancer cells play for maximal survival is to drive the transformation of cells that co-exist with cancer cells within the tumor microenvironment (TME). Two major types of cells are subjected to such transformation by cancer cells. Fibroblasts are converted to cancer-associated fibroblasts (CAF) and macrophages become tumor-associated macrophages (TAM). Upon this transformation, both cell types begin to aid and abet cancer cells in proliferation and metastasis.
These schemes by cancer cells turn functional fighter cells into bystanders, which makes effective cancer treatment challenging. Such challenges add to the urgency of cancer vaccine development, vaccines that are preventive and therapeutic against cancer.
