Tissue-Dependent Tumor Microenvironments and Their Impact on Immunotherapy Responses

Abstract

Recent advances in cancer immunology have led to a better understanding of the role of the tumor microenvironment (TME) in tumor initiation, progression, and metastasis. Tumors can occur at many locations within the body and coevolution between malignant tumor cells and non-malignant cells sculpts the TME at these sites. It has become increasingly clear that there are specific differences of the TMEs at different anatomical locations, and these tissue-specific TMEs regulate tumor growth, determine metastatic progression, and impact on the outcome of therapy responses. Herein, we review the scientific advances in understanding tissue-specific TMEs, discuss their impact on immunotherapeutic response, and assess the current clinical knowledge in this emerging field. A deeper understanding of the tissue-specific TME will help to develop effective immunotherapies against tumors and their metastases and assist in predicting clinical outcomes.

Keywords: anticancer therapy; immunosuppression; immunotherapy; tissue-specific microenvironment; tumor microenvironment.

Figure 1

The immunosuppressive tumor microenvironment. Various immunosuppressive cell types exist within the TME including TAMs, MDSCs, Tregs, and CAFs. Tumor-derived chemokines and the metabolic tumor environment recruit or polarize these cells to a protumor, immunosuppressive phenotype. Suppression of the antitumor immune response occurs partly through the release of immunosuppressive molecules such as TGF-β, IL-10, IDO, Arg1, ROS, and NO. Abbreviations: Arg1, arginase1; CAFs, cancer-associated fibroblasts; DC, dendritic cell; ECM, extracellular matrix; Eff T cell, effector T cell; IDO, idoleamine 2,3-dioxygenase; MDSCs, myeloid-derived suppressor cells; ROS, reactive oxygen species; NO, nitric oxide; TAMs, tumor-associated macrophages; Tregs, regulatory T cells.

Figure 2

Tissue-specific tumor microenvironment (TME). Tumors can occur at various sites in the body and often occur simultaneously, for example, by metastatic growth. The normal tissue-specific microenvironment consists of both tissue-specific cell types and tissue-resident cell types such as immune, mesenchymal, and endothelial cells. Upon tumor initiation or metastatic colonization, interactions occur between tumor and normal cells. During tumor development, these interactions are partly responsible for the established TME. Both preclinical and clinical studies suggest that the tissue-specific TME mediates the response to immunotherapy. In addition, tumors occurring simultaneously within different TMEs can cross talk and influence each other. Thus, the normal tissue plays a major role in sculpting the established TME and this ultimately impacts on the response to immunotherapy.