Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.

Abstract

Regulatory T cells (Tregs) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8+ T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from Treg-depleted mice were cultured in this system. Experiments with neutralizing antibodies showed that blocking transforming growth factor-β (TGF-β) also prevented immunosuppression. Immunosuppression depended on cell-cell contact or cellular proximity because soluble factors from the collagen-fibrin gel cultures did not inhibit tumor cell killing by T cells. Moreover, intravital, two-photon microscopy showed that tumor-specific Pmel-1 effector T cells physically interacted with tumor-resident Tregs in mice. Tregs isolated from B16 tumors alone were sufficient to suppress CD8+ T cell-mediated killing, which depended on surface-bound TGF-β on the Tregs Immunosuppression of CD8+ T cells correlated with a decrease in the abundance of the cytolytic protein granzyme B and an increase in the cell surface amount of the immune checkpoint receptor programmed cell death protein 1 (PD-1). These findings suggest that contact between Tregs and antitumor T cells in the tumor microenvironment inhibits antimelanoma immunity in a TGF-β-dependent manner and highlight potential ways to inhibit intratumoral Tregs therapeutically.

• Authors: Sadna Budhu, David A Schaer, Yongbiao Li, Ricardo Toledo-Crow, Katherine Panageas, Xia Yang, Hong Zhong, Alan N Houghton, Samuel C Silverstein, Taha Merghoub, Jedd D Wolchok
• Journal: Science signaling (Sci Signal) Vol. 10 Issue 494 (Aug 29 2017) ISSN: 1937-9145 [Electronic] United States
• PMID: 28851824 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Antibodies, Neutralizing
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Transforming Growth Factor beta
• Granzymes

Topics

• Animals
• Antibodies, Neutralizing (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Communication
• Cell Line, Tumor
• Coculture Techniques
• Female
• Granzymes (metabolism)
• Immunity, Cellular
• Immunosuppression Therapy
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Programmed Cell Death 1 Receptor (metabolism)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Microenvironment (immunology)