title: Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors.
abstract: Foxp3(+) regulatory T (T(reg)) cells are dominant suppressor cells which regulate conventional T (T(conv)) cells. Inside tumor microenvironment, T(reg) cells have been known to become potent in suppressing T(conv) cell responses, thereby enabling tumor cells to circumvent immune response. However, the underlying mechanism by which tumor-infiltrating T(reg) cells display enhanced suppressive function is still unresolved. To understand characteristics and function of tumor-infiltrating T(reg) cells as well as T(conv) cells in the tumor site, we analyzed their phenotypes either within tumor burden or at distant site of tumor using both heterotopic and orthotopic mouse cancer models. Compared to CD8(+) T cells at distant site of tumor, tumor-infiltrating CD8(+) T cells dramatically upregulated programmed death 1 (PD-1) and other inhibitory receptors, thereby being more exhausted functionally. Tumor-infiltrating CD4(+) T cells also expressed higher level of PD-1 than CD4(+) T cells at distant site of tumor but very surprisingly, upregulation of PD-1 occurred in CD4(+)Foxp3(+) T(reg) as well as CD4(+)Foxp3(-) T(conv) cells. Moreover, tumor infiltrating T(reg) cells upregulated other inhibitory receptors such as T cell immunoglobulin mucin 3 (TIM-3), cytotoxic T lymphocyte antigen-4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and lymphocyte activation gene-3 (LAG-3). These results suggest that upregulation of PD-1 and other inhibitory receptors on tumor-infiltrating T(reg) cells is related with their enhanced suppressive function.
authors.affiliation: Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Anthony
authors.initials: A
authors.lastname: Kusnadi
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lee
authors.forename: Won Woo
authors.initials: WW
authors.lastname: Kim
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
authors.forename: Ik Jae
authors.initials: IJ
authors.lastname: Lee
authors.forename: Jinsil
authors.initials: J
authors.lastname: Seong
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000276:immunology; D019139:Tumor Escape; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; C106544:Tnfrsf18 protein, mouse; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse