Abstract
Our understanding of the tumor microenvironment (TME), including the interplay between tumor cells, stromal cells, immune cells, and extracellular matrix components, is mandatory for the innovation of new therapeutic approaches in cancer. The cell-cell communication within the TME plays a pivotal role in the evolution and progression of cancer. Cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) are major cell populations in the stroma of all solid tumors and often exert protumorigenic functions; however, the origin and precise functions of CAF and TAM are still incompletely understood. CAF and TAM hold significant potential as therapeutic targets to improve outcomes in oncology when combined with existing therapies. The regulation of CAF/TAM communication and/or their differentiation could be of high impact for improving the future targeted treatment strategies. Nevertheless, there is much scope for research and innovation in this field with regards to the development of novel drugs. In this review, we elaborate on the current knowledge on CAF and TAM in cancer and cancer immunotherapy. Additionally, by focusing on their heterogenous functions in different stages and types of cancer, we explore their role as potential therapeutic targets and highlight certain aspects of their functions that need further research.
Highlights
Originating from the neighboring healthy tissues and recruited from the circulation, a multitude of proliferating non-neoplastic cells such as fibroblasts, macrophages, immune cells, and endothelial cells contribute to carcinogenesis within the tumor microenvironment (TME) [1]
Cancer-Associated Fibroblasts and Tumor-Associated Macrophages that interfere with Cancer-associated fibroblasts (CAF)/tumor-associated macrophages (TAM) interactions, and their combinations hereof, are highly prioritized in experimental clinical regimens that are aimed at modulating the TME [8]
In mouse models of melanoma, colon carcinoma, and lymphoma, dual targeting of CD47 and PD-L1 was found to enhance anti-tumor effects [163,164,165] and several clinical trials evaluating the efficacy of CD47 or signal regulatory protein alpha (SIRPa) monoclonal antibodies as monotherapy or in combination with immune checkpoint inhibitors are underway (Table 5; ClinicalTrials.gov)
Summary
Originating from the neighboring healthy tissues and recruited from the circulation, a multitude of proliferating non-neoplastic cells such as fibroblasts, macrophages, immune cells, and endothelial cells contribute to carcinogenesis within the tumor microenvironment (TME) [1]. Cancerassociated fibroblasts (CAF) and tumor-associated macrophages (TAM) are the major cell populations within the stroma of all solid tumors in which they often exert protumorigenic functions. Their precise interactions remain to be elucidated, CAF and TAM strongly modulate disease progression, therapy resistance, and clinical outcomes [2,3,4,5,6,7] and may function in synergy. Cancer-Associated Fibroblasts and Tumor-Associated Macrophages that interfere with CAF/TAM interactions, and their combinations hereof, are highly prioritized in experimental clinical regimens that are aimed at modulating the TME [8]
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