Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors

Cell Immunol. Jul-Aug 2012;278(1-2):76-83. doi: 10.1016/j.cellimm.2012.07.001. Epub 2012 Jul 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology*
  • CD4 Antigens / immunology
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Cell Movement / immunology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Glucocorticoid-Induced TNFR-Related Protein / genetics
  • Glucocorticoid-Induced TNFR-Related Protein / immunology
  • Hepatitis A Virus Cellular Receptor 2
  • Male
  • Mice
  • Myeloid Cells / immunology
  • Myeloid Cells / pathology
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology*
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Tumor Burden / immunology
  • Tumor Escape
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*
  • Up-Regulation

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CD223 antigen
  • CD4 Antigens
  • CTLA-4 Antigen
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Glucocorticoid-Induced TNFR-Related Protein
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus
  • Tnfrsf18 protein, mouse