Tumor microenvironment antigens

The identification and characterization of tumor antigens are central objectives in developing anti-cancer immunotherapy. Traditionally, tumor-associated antigens (TAAs) are considered relatively restricted to tumor cells (i.e., overexpressed proteins in tumor cells), whereas tumor-specific antigens (TSAs) are considered unique to tumor cells. Recent studies have focused on identifying patient-specific neoantigens, which might be highly immunogenic because they are not expressed in normal tissues. The opposite strategy has emerged with the discovery of anti-regulatory T cells (anti-Tregs) that recognize and attack many cell types in the tumor microenvironment, such as regulatory immune cells, in addition to tumor cells. The term proposed in this review is tumor microenvironment antigens (TMAs) to describe the antigens that draw this attack. As therapeutic targets, TMAs offer several advantages that differentiate them from more traditional tumor antigens. Targeting TMAs leads not only to a direct attack on tumor cells but also to modulation of the tumor microenvironment, rendering it immunocompetent and tumor-hostile. Of note, in contrast to TAAs and TSAs, TMAs also are expressed in non-transformed cells with consistent human leukocyte antigen (HLA) expression. Inflammation often induces HLA expression in malignant cells, so that targeting TMAs could additionally affect tumors with no or very low levels of surface HLA expression. This review defines the characteristics, differences, and advantages of TMAs compared with traditional tumor antigens and discusses the use of these antigens in immune modulatory vaccines as an attractive approach to immunotherapy. Different TMAs are expressed by different cells and could be combined in anti-cancer immunotherapies to attack tumor cells directly and modulate local immune cells to create a tumor-hostile microenvironment and inhibit tumor angiogenesis. Immune modulatory vaccines offer an approach for combinatorial therapy with additional immunotherapy including checkpoint blockade, cellular therapy, or traditional cancer vaccines. These combinations would increase the number of patients who can benefit from such therapeutic measures, which all have optimal efficiency in inflamed tumors.

Automated summary

Identifying and characterizing tumor antigens are crucial for developing anti-cancer immunotherapy. Traditional tumor-associated antigens (TAAs) are mainly expressed in tumor cells, while tumor-specific antigens (TSAs) are unique to tumor cells. Recent studies have focused on patient-specific neoantigens, which are highly immunogenic due to their absence in normal tissues. In addition, the discovery of anti-regulatory T cells (anti-Tregs) has led to the identification of tumor microenvironment antigens (TMAs) that can be targeted for immunotherapy. TMAs not only directly attack tumor cells but also modulate the tumor microenvironment, making it more immunocompetent and hostile to tumors. Unlike TAAs and TSAs, TMAs are also expressed in non-transformed cells, providing the opportunity to affect tumors with low levels of surface human leukocyte antigen (HLA) expression. This review discusses the characteristics, differences, and advantages of TMAs compared to traditional tumor antigens and highlights the potential of using TMAs in immune modulatory vaccines as a promising approach to immunotherapy.