In a healthy individual, the immune system recognizes and destroys foreign substances (e.g. infectious agents) or cancerous cells. Defects in the immune system’s ability to identify cancer cells leads to disease progression.

 The aim of cancer immunotherapy is to elicit a robust immune response to search, recognize, engage, and eradicate cancer cells. However, there are a host of factors including the tumor microenvironment (TME) that impedes the immune response to tumors.

The Problem

What is the TME?

The tumor microenvironment consists of cellular components of the tumor, the surrounding extracellular matrix, and interstitial

fluid. These factors interact with each other, contributing to the hallmarks of cancer,1 and have a significant influence on immune responses against the tumor. The cellular components in the tumor include tumor cells themselves, associated stromal cells such as fibroblasts, endothelial cells, and infiltrating immune cells. The infiltrating immune cells play an essential role in immune responses against cancer. For example, subsets of immune cells such as cytotoxic T lymphocytes and natural killer (NK) cells inhibit tumor growth.

Immune aspects of the TME

Other infiltrating immune cells may either assist in tumor growth (e.g., tumor associated macrophages (TAMs), neutrophils, and mast cells) or inhibit immune reactions against tumor cells (e.g., regulatory T cells and myeloid-derived suppressor cells [MDSCs]). These tumors and non-tumor cells express molecules on their cell surfaces and secrete extracellular matrix components, growth factors, cytokines, chemokines, proteases, other enzymes, and metabolites. that may affect the effectiveness of tumor immunotherapy.

Other characteristics of the tumor microenvironment may significantly influence T-cell immune responses against cancers. For example, hypoxia has been shown to inhibit T-cell receptor (TCR) and CD28-mediated activation of T lymphocytes, in addition to indirectly recruiting regulatory T cells, which may suppress T-cell immune responses. In addition, low extracellular pH, low glucose concentration and aberrant vasculature may affect T-cell trafficking, infiltration, and function. This is a dynamic relationship in which the tumor shapes its microenvironment,influencing T-cell activity, while a balance between pro- and anti-malignancy factors in the microenvironment regulate the growth of the tumor.

Challenges with Existing Systems

While current in vitro and in vivo translational systems are valuable tools to study these factors, there are several disadvantages ranging from physiological relevance, downregulation of antigen presentation and quality of cell lines and patient derived samples.

  • Production of TGFβ by tumor cells leading to impairment of T cell function.

  • Downregulation of HLA class I on tumor cells in vivo leading to absence of tumor lysis by T cells.

  • Absence of co-stimulatory molecules on tumor cells leading to impairment of CTL induction by direct tumor stimulation.

  • Expression of Fas ligand by tumor cells leading to inactivation of Fas receptor-positive CTL.

  • Emergence of epitope/Ag loss variant tumor cells after tumor lysis by CTL in vivo.

  • Downregulation of zeta chain in CTL leading to loss of function.