Immunotherapy and tumor microenvironment

Abstract

Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases.

Keywords: CAR T-cell therapy; Checkpoint blockade; Chemokine; Cytokine; Tumor microenvironment; Tumor-infiltrating immune cells.

Figure 1. Immunotherapy and the tumor microenvironment (TME)

A successful tumor control induced by immunotherapy requires the activation of the immune system, expansion of the effector cells, infiltration of activated effector cells to the tumor tissue, and destruction of the tumor cells. Tumor barriers can greatly dampen those processes, while immunotherapy aims to enhance them. Effector T cells can be inhibited by checkpoint molecules, such as PDL1, expressed in the TME. The inhibition by PDL1 can be overcome by anti-PD1/PDL1. Stimulatory checkpoint antibodies are used to activate immune cells. But some antibody, eg anti-CD40, can also work on stroma cells for optimized tumor control. The ECM forms a barrier preventing T cells reach to the TME for tumor destruction. However, the infiltration can be enhanced by inducing/delivering cytokines/chemokines to the TME.