Tumor Microenvironment and Cancer Immunity
The tumor microenvironment (TME) consists of specialized tumor vasculature and a mixture of cancer-associated fibroblasts, pericytes, endothelial cells, together with other specialized stromal cells types, like the tumor-associated macrophages producing tumor- suppressive factors. These cells are all recruited by the tumor cells to the primary tumor site.
The tumor progression is profoundly influenced by and dependent upon the tumor-TME interaction. This interaction ultimately determines whether the primary tumor becomes eradicated, metastasizes, and establishes micrometastases.
Most TMEs of solid cancers harbor specialized stromal cells that secrete factors and extracellular matrix proteins endowing the tumor cells with molecular cues that further the oncogenic phenotype.
The cellular composition of the TME influences the promotion of tumor growth and angiogenesis, the remodeling of the extracellular matrix, and directs cell-cell interactions.
The collective phenotype of the TME is decisive for tumor progression, like proliferation, migration, and multidrug resistance.
Figure 1: CD163 immunohistochemical staining of human liver cancer using the Anti-CD163 polyclonal Antibody (HPA051974) showing strong immunoreactivityin brown. Figure 2: FOXP3 (forkhead box P3) immunofluorescent staining of human cell line PC-3 using the Anti-FOXP3 polyclonal antibody (HPA045943) showing selective localization to nucleoplasm in green. Figure 3: FN1 (fibronectin1) immunohistochemical staining of human colorectal cancer using the Anti-FN1 polyclonal antibody (HPA027066) showing strong immunoreactivity in brown.
Immunogenic tumors also host resident and tumor-infiltrating T-cells (TILs). TILs are attracted to and accumulate within the TME at the border or within the tumors due to their surface expression of altered self-antigens, i.e. neoantigens. The T-cells recognize the unique, altered-self neoantigen presented on the surface of antigen-presenting cells in a Human Leukocyte Antigen (HLA) restricted manner.
Dominant tumor neoantigens are encoded by “driver” mutations being particularly immunogenic since they are recognized by cytotoxic TILs destined to attack and eliminate cancer. The presence of immunosuppressive regulatory T-cells (T-regs) is indicative of immunotherapy resistance. Furthermore, massive stroma- formation (desmoplasia), associated with the solid tumor, provides a robust physical barrier against immune-infiltration.
Immunotherapy, using immune checkpoint inhibitors or strategies designed to harness the immune system, remains the
most crucial strategy for the treatment of malignant cancers with a dismal prognosis. Hence the revolutionizing immunotherapeutic application of immune checkpoint inhibitors like anti-PD-1, anti- PD-L1, or anti-CTLA4A has opened up novel avenues for therapeutic immune checkpoint inhibitors to unleash the anti- tumorresponse.
Unfortunately, resistance against immune checkpoint inhibition remains a common cause of anti-tumor immunotherapy failure. The phenomenon is partly due to the expansion of anti-tumorigenic or immunosuppressive T-cells that express immune checkpoint inhibitor proteins.
Many anti-cancer immunotherapies did fail due to the escape of transformed cells from T-cell mediated killing. This escape is, among other things, caused by shedding of tumor antigens from tumor cells surfaces and/or a subthreshold antigen exposure unable to trigger or sustain animmunological response.
Readings
- Bashar Emon et al. (2018) Biophysics of Tumor Microenvironment and Cancer Metastasis - A Mini Review Computational and Structural Biotechnology Journal 16: 279-287
- Frances R. et al., (2012) The tumor microenvironment at a glance. Journal of Cell Science 125: 5591-5596
- Gregory L. et al. (2015) Immune Escape Mechanisms as a Guide for Cancer Immunotherapy. Clin Cancer Res. 21(4):687-692
- Ribatti D. (2017) The concept of immune surveillance against tumors: The first theories. Oncotarget 8(4):7175–7180.
- Wang M. et al. (2017) Role of tumor microenvironment in tumorigenesis. J Cancer. 8(5): 761–773
- Yin Z. et al. (2019) Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy.
J Exp&Clin Cancer Res 38:403 - Yuan Y. et al. (2016) Role of the tumor microenvironment in tumor progression and the clinical applications (Review) Oncology Reports 35(5): 2499-2515