PMID- 36175673 OWN - NLM STAT- MEDLINE DCOM- 20230425 LR - 20230714 IS - 1863-2300 (Electronic) IS - 1863-2297 (Print) IS - 1863-2297 (Linking) VI - 45 IP - 2 DP - 2023 Mar TI - Tumor microenvironment antigens. PG - 253-264 LID - 10.1007/s00281-022-00966-0 [doi] AB - 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. CI - (c) 2022. The Author(s). FAU - Andersen, Mads Hald AU - Andersen MH AUID- ORCID: 0000-0002-2914-9605 AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital Herlev, Borgmester Ib Juuls Vej 25C, 5th floor, DK-2730, Herlev, Denmark. mads.hald.andersen@regionh.dk. AD - Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. mads.hald.andersen@regionh.dk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20220929 PL - Germany TA - Semin Immunopathol JT - Seminars in immunopathology JID - 101308769 RN - 0 (Antigens, Neoplasm) RN - 0 (Cancer Vaccines) SB - IM MH - Humans MH - Antigens, Neoplasm MH - Tumor Microenvironment MH - *Neoplasms/therapy/drug therapy MH - Immunotherapy MH - T-Lymphocytes, Regulatory MH - *Cancer Vaccines PMC - PMC10335965 OTO - NOTNLM OT - Anti-Tregs OT - Anti-regulatory T cells OT - Arginase OT - IDO OT - Immune modulatory vaccine OT - PD-L1 OT - TGF-beta OT - TMA OT - Tumor microenvironment antigens COIS- MHA is a shareholder and scientific advisor of IO Biotech ApS. EDAT- 2022/09/30 06:00 MHDA- 2023/04/25 06:42 PMCR- 2022/09/29 CRDT- 2022/09/29 23:35 PHST- 2022/07/07 00:00 [received] PHST- 2022/09/16 00:00 [accepted] PHST- 2023/04/25 06:42 [medline] PHST- 2022/09/30 06:00 [pubmed] PHST- 2022/09/29 23:35 [entrez] PHST- 2022/09/29 00:00 [pmc-release] AID - 10.1007/s00281-022-00966-0 [pii] AID - 966 [pii] AID - 10.1007/s00281-022-00966-0 [doi] PST - ppublish SO - Semin Immunopathol. 2023 Mar;45(2):253-264. doi: 10.1007/s00281-022-00966-0. Epub 2022 Sep 29.