Tumor Microenvironment Immunosuppression: A Roadblock to CAR T-Cell Advancement in Solid Tumors

Abstract

Chimeric antigen receptor (CAR) T cells are an exciting advancement in cancer immunotherapy, with striking success in hematological cancers. However, in solid tumors, the unique immunosuppressive elements of the tumor microenvironment (TME) contribute to the failure of CAR T cells. This review discusses the cell populations, cytokine/chemokine profile, and metabolic immunosuppressive elements of the TME. This immunosuppressive TME causes CAR T-cell exhaustion and influences failure of CAR T cells to successfully infiltrate solid tumors. Recent advances in CAR T-cell development, which seek to overcome aspects of the TME immunosuppression, are also reviewed. Novel discoveries overcoming immunosuppressive limitations of the TME may lead to the success of CAR T cells in solid tumors.

Keywords: CAR T cell; CAR T-cell exhaustion; TME; cancer; chimeric antigen receptor; immunosuppression; immunotherapy; solid tumor; tumor microenvironment.

Figure 1

CAR T-cell structure and effector mechanism. CAR T cells are composed of a CD8+ T cell with a CAR construct, which is composed of scFv, transmembrane, and activation domains. CAR T cells bind to their specific antigen on cancer cells, activating cytotoxic function (directional release of perforin/granzymes or Fas/FasL interaction), killing the cancer cell.

Figure 2

The heterogenous tumor environment. Tumors are comprised of a variety of cell types, as shown above. The ECM and CAF form a barrier that separates the tumor from the surrounding tissue. The vasculature of the TME often is insufficient for the constant proliferation and tumor growth.

Figure 3

Immunosuppressive effects on CAR T cells. (A) CAR T cells can fail to infiltrate solid tumors due to lack of blood vessel penetration into the tumor, the barrier surrounding the tumor comprised of the ECM and CAFs, and down-regulation of extravasation mediators needed to leave the blood vessels. (B) Metabolic-induced exhaustion caused by increased glycolysis of cancer cells results in low nutrient levels and high waste levels. This metabolic environment impairs T-cell activation and cytotoxic function. (C) Chronic antigen stimulation from abundant cancer cells in the TME can lead to anergy and exhaustion of CAR T cells. (D) Heterogenous cancer cell populations with varying antigens and selective pressure can lead to antigen escape, where cancer cells will evolve not to express the antigen the CAR T cell binds to.