Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer
Nicholas A. Taylor, … , Benjamin G. Vincent, Jonathan S. Serody
Nicholas A. Taylor, … , Benjamin G. Vincent, Jonathan S. Serody
Published August 21, 2017
Citation Information: J Clin Invest. 2017;127(9):3472-3483. https://doi.org/10.1172/JCI90499.
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Research Article Immunology Oncology

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

Abstract

Claudin-low breast cancer is an aggressive subtype that confers poor prognosis and is found largely within the clinical triple-negative group of breast cancer patients. Here, we have shown that intrinsic and immune cell gene signatures distinguish the claudin-low subtype clinically as well as in mouse models of other breast cancer subtypes. Despite adaptive immune cell infiltration in claudin-low tumors, treatment with immune checkpoint inhibitory antibodies against cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1) were ineffective in controlling tumor growth. CD4+FoxP3+ Tregs represented a large proportion of the tumor-infiltrating lymphocytes (TILs) in claudin-low tumors, and Tregs isolated from tumor-bearing mice were able to suppress effector T cell responses. Tregs in the tumor microenvironment highly expressed PD-1 and were recruited partly through tumor generation of the chemokine CXCL12. Antitumor efficacy required stringent Treg depletion combined with checkpoint inhibition; delays in tumor growth were not observed using therapies that modestly diminished the number of Tregs in the tumor microenvironment. This study provides evidence that the recruitment of Tregs to the tumor microenvironment inhibits an effective antitumor immune response and highlights early Treg recruitment as a possible mechanism for the lack of response to immune checkpoint blockade antibodies in specific subtypes of cancer that are heavily infiltrated with adaptive immune cells.

Authors

Nicholas A. Taylor, Sarah C. Vick, Michael D. Iglesia, W. June Brickey, Bentley R. Midkiff, Karen P. McKinnon, Shannon Reisdorf, Carey K. Anders, Lisa A. Carey, Joel S. Parker, Charles M. Perou, Benjamin G. Vincent, Jonathan S. Serody

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Figure 2

T11 and T12 (claudin-low) tumors recruit elevated numbers of immune cells to the tumor site.

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T11 and T12 (claudin-low) tumors recruit elevated numbers of immune cell...
WT mice were injected with 1 × 106 2250 tumor cells or 1 × 104 T11 or T12 cells. Neu-N mice were injected with 5 × 104 NT2 cells. Tumors were harvested at 20 mm2 (2250, n = 9; NT2, n = 10; T11, n = 12) (A–D) or 100 mm2 (2250, n = 10; NT2, n = 5; T11, n = 10; T12, n = 6) (E–H), digested, enriched for lymphocytes, and analyzed by FACS. (A) CD4+ TILs, 20 mm2. (B) CD8+ TILs, 20 mm2. (C) CD19+ TILs, 20 mm2 (2250, n = 4). (D) CD4+FoxP3+ TILs, 20 mm2. (E) CD4+ TILs, 100 mm2. (F) CD8+ TILs, 100 mm2. (G) CD19+ TILs, 100 mm2. (H) CD4+FoxP3+ TILs, 100 mm2. (I) Correlation between the percentage of CD8+ T cells and FoxP3+CD4+ T cells in mice with 20 mm2 T11 tumors. n = 16 mice. (J) Correlation between CD19+ B cells and FoxP3+CD4+ T cells in T11 mice with 20 mm2 tumors. n = 16 (taken from the same group as evaluated in I). Statistical significance determined by Kruskal-Wallis test with Dunn’s post-test for multiple comparisons. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.