CAR T Cell Locomotion in Solid Tumor Microenvironment

Abstract

The promising outcomes of chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies potentiates its capability in the fight against many cancers. Nevertheless, this immunotherapy modality needs significant improvements for the treatment of solid tumors. Researchers have incrementally identified limitations and constantly pursued better CAR designs. However, even if CAR T cells are armed with optimal killer functions, they must overcome and survive suppressive barriers imposed by the tumor microenvironment (TME). In this review, we will discuss in detail the important role of TME in CAR T cell trafficking and how the intrinsic barriers contribute to an immunosuppressive phenotype and cancer progression. It is of critical importance that preclinical models can closely recapitulate the in vivo TME to better predict CAR T activity. Animal models have contributed immensely to our understanding of human diseases, but the intensive care for the animals and unreliable representation of human biology suggest in vivo models cannot be the sole approach to CAR T cell therapy. On the other hand, in vitro models for CAR T cytotoxic assessment offer valuable insights to mechanistic studies at the single cell level, but they often lack in vivo complexities, inter-individual heterogeneity, or physiologically relevant spatial dimension. Understanding the advantages and limitations of preclinical models and their applications would enable more reliable prediction of better clinical outcomes.

Keywords: 3D in vitro models; CAR T cells; T cell migration; adoptive T cell therapy; immunotherapy; solid tumors; trafficking; tumor microenvironment.

Figure 1

The exhausting journey of CAR T cells in the TME: In this journey, CAR T cells must be able to detect chemokines at the tumor site, effectively roll and adhere to the blood vessel wall, initiate transendothelial migration, and invade the tumor stroma. Here, the immune cells must overcome various biochemical and physical barriers to then encounter pro-tumor cells that suppress CAR T cell activity. Some CAR T cells may eventually make contact with target cancer cells that express abundant immune checkpoints, further reducing anti-tumor function.

Figure 2

Overview of the immunosuppressive tumor microenvironment (TME) and important contributors to tumor progression: Within the TME, there is a dynamic relationship between peritumoral and intratumoral components that include immune cells, cancer cells, and the stromal elements often exhibiting context-dependent functionality. Different components of the TME carry out pro- or anti-tumor functions, and such polarizations are caused by reciprocal interactions with physical and biochemical cues from the surroundings. The polarized functions are not distinctive but rather heterogenous contributing to an immunosuppressive TME [5,19,20,28,29,35,39,40,46,48,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75].