Folr2, also known as folate receptor 2, is a type of folate transporter. Folates are B vitamins involved in one-carbon metabolism, and Folr2 has been implicated in various biological processes related to immune-related functions. It is expressed in specific macrophage subsets, suggesting its role in modulating immune responses [6,7].

In cancer research, Folr2 + macrophages have shown distinct functions. In breast cancer, they localize in perivascular areas of the tumor stroma, interact with CD8 + T cells, and efficiently prime effector CD8 + T cells ex vivo, with their density positively correlating with better patient survival [1]. In hepatocellular carcinoma, fetal-like (FOLR2) tumor-associated macrophages are part of an onco-fetal reprogramming of the tumor microenvironment [2]. In chronic kidney disease, a pro-inflammatory fibroblast population promotes the switch of macrophages into FOLR2 + macrophages, and their interaction is involved in fibrosis [3]. In colon cancer, a subset of FOLR2 + macrophages is embedded in plasma cell niches [4]. In gastric cancer, FOLR2 + macrophages possess antitumor immune potential, and their proportion decreases during the progression from intestinal metaplasia to early gastric cancer [5]. In lung adenocarcinoma, FOLR2-expressing tumor-associated macrophages are involved in the formation of an immunosuppressive microenvironment [8]. Also, TIM4 + FOLR2 + macrophages in tertiary lymphoid structures are associated with an active immune infiltrate across several cancer types, with a specific subset correlating with a better prognosis [9].

In conclusion, Folr2, through its expression in specific macrophage subsets, plays a crucial role in modulating immune responses in various disease conditions, especially in cancers and chronic kidney disease. The study of Folr2 in these contexts helps in understanding the underlying immune-related mechanisms and provides potential targets for therapeutic interventions.

References:

1. Nalio Ramos, Rodrigo, Missolo-Koussou, Yoann, Gerber-Ferder, Yohan, Piaggio, Eliane, Helft, Julie. 2022. Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer. In Cell, 185, 1189-1207.e25. doi:10.1016/j.cell.2022.02.021. https://pubmed.ncbi.nlm.nih.gov/35325594/

2. Sharma, Ankur, Seow, Justine Jia Wen, Dutertre, Charles-Antoine, Ginhoux, Florent, DasGupta, Ramanuj. 2020. Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. In Cell, 183, 377-394.e21. doi:10.1016/j.cell.2020.08.040. https://pubmed.ncbi.nlm.nih.gov/32976798/

3. Cohen, Camille, Mhaidly, Rana, Croizer, Hugo, Ju, Wenjun, Mechta-Grigoriou, Fatima. 2024. WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease. In Nature communications, 15, 743. doi:10.1038/s41467-024-44886-z. https://pubmed.ncbi.nlm.nih.gov/38272907/

4. Matusiak, Magdalena, Hickey, John W, van IJzendoorn, David G P, West, Robert B, van de Rijn, Matt. . Spatially Segregated Macrophage Populations Predict Distinct Outcomes in Colon Cancer. In Cancer discovery, 14, 1418-1439. doi:10.1158/2159-8290.CD-23-1300. https://pubmed.ncbi.nlm.nih.gov/38552005/

5. He, Yuxin, Wang, Jiayu, Deng, Zilin, Shi, Tongguo, Chen, Weichang. 2024. FOLR2+ macrophage depletion from intestinal metaplasia to early gastric cancer: single-cell sequencing insight into gastric cancer progression. In Journal of experimental & clinical cancer research : CR, 43, 326. doi:10.1186/s13046-024-03245-y. https://pubmed.ncbi.nlm.nih.gov/39702278/

6. Nawaz, Fathima Zahra, Kipreos, Edward T. 2022. Emerging roles for folate receptor FOLR1 in signaling and cancer. In Trends in endocrinology and metabolism: TEM, 33, 159-174. doi:10.1016/j.tem.2021.12.003. https://pubmed.ncbi.nlm.nih.gov/35094917/

7. Dick, Sarah A, Wong, Anthony, Hamidzada, Homaira, Mak, Tak W, Epelman, Slava. 2022. Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles. In Science immunology, 7, eabf7777. doi:10.1126/sciimmunol.abf7777. https://pubmed.ncbi.nlm.nih.gov/34995099/

8. Xiang, Chan, Zhang, Min, Shang, Zhanxian, Yu, Yang, Han, Yuchen. 2023. Single-cell profiling reveals the trajectory of FOLR2-expressing tumor-associated macrophages to regulatory T cells in the progression of lung adenocarcinoma. In Cell death & disease, 14, 493. doi:10.1038/s41419-023-06021-6. https://pubmed.ncbi.nlm.nih.gov/37532692/

9. Bugatti, Mattia, Bergamini, Marco, Missale, Francesco, Benvenuti, Federica, Vermi, William. . A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types. In Cancer immunology research, 10, 1340-1353. doi:10.1158/2326-6066.CIR-22-0271. https://pubmed.ncbi.nlm.nih.gov/36122412/