Vick et al. used a murine claudin-low breast cancer model expressing high levels of PD-1 on Tregs to investigate mechanisms underlying the poor response of TNBC tumors to anti-PD-1 therapy. Transcript profiles of Tregs isolated from mice treated with anti-PD-1 showed increased expression of Jun, Fos, Bcl-2, and Foxp3 compared to control Tregs, which was associated with increased Treg proliferation, protection from glucocorticoid-induced apoptosis, and enhanced suppressive function in ex vivo assays. Thus, even in tumors well infiltrated with immune cells, high levels of PD-1-expressing Tregs in the TME could negatively impact checkpoint inhibition outcomes.
Contributed by Katherine Turner
ABSTRACT: We have previously shown in a model of claudin-low breast cancer that regulatory T cells (T(regs)) are increased in the tumor microenvironment (TME) and express high levels of PD-1. In mouse models and patients with triple-negative breast cancer, it is postulated that one cause for the lack of activity of anti-PD-1 therapy is the activation of PD-1-expressing T(regs) in the TME. We hypothesized that the expression of PD-1 on T(regs) would lead to enhanced suppressive function of T(regs) and worsen antitumor immunity during PD-1 blockade. To evaluate this, we isolated T(regs) from claudin-low tumors and functionally evaluated them ex vivo. We compared transcriptional profiles of T(regs) isolated from tumor-bearing mice with or without anti-PD-1 therapy using RNA sequencing. We found several genes associated with survival and proliferation pathways; for example, Jun, Fos, and Bcl2 were significantly upregulated in T(regs) exposed to anti-PD-1 treatment. Based on these data, we hypothesized that anti-PD-1 treatment on T(regs) results in a prosurvival phenotype. Indeed, T(regs) exposed to PD-1 blockade had significantly higher levels of Bcl-2 expression, and this led to increased protection from glucocorticoid-induced apoptosis. In addition, we found in vitro and in vivo that T(regs) in the presence of anti-PD-1 proliferated more than control T(regs) PD-1 blockade significantly increased the suppressive activity of T(regs) at biologically relevant T(reg)/T(naive) cell ratios. Altogether, we show that this immunotherapy blockade increases proliferation, protection from apoptosis, and suppressive capabilities of T(regs), thus leading to enhanced immunosuppression in the TME.
Author Info: (1) Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC. (2) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill,
Author Info: (1) Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC. (2) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and. (3) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and. Department of Genetics, University of North Carolina, Chapel Hill, NC. (4) Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC; jonathan_serody@med.unc.edu. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and.
