Non-conventional Inhibitory CD4+Foxp3-PD-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity

Roberta Zappasodi; Sadna Budhu; Matthew D Hellmann; Michael A Postow; Yasin Senbabaoglu; Sasikanth Manne; Billel Gasmi; Cailian Liu; Hong Zhong; Yanyun Li; Alexander C Huang; Daniel Hirschhorn-Cymerman; Katherine S Panageas; E John Wherry; Taha Merghoub; Jedd D Wolchok

doi:10.1016/j.ccell.2018.05.009

Non-conventional Inhibitory CD4⁺Foxp3^-PD-1^hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity

Cancer Cell. 2018 Jun 11;33(6):1017-1032.e7. doi: 10.1016/j.ccell.2018.05.009.

Authors

Roberta Zappasodi¹, Sadna Budhu², Matthew D Hellmann³, Michael A Postow⁴, Yasin Senbabaoglu², Sasikanth Manne⁵, Billel Gasmi², Cailian Liu², Hong Zhong², Yanyun Li², Alexander C Huang⁶, Daniel Hirschhorn-Cymerman², Katherine S Panageas⁷, E John Wherry⁶, Taha Merghoub⁸, Jedd D Wolchok⁹

Affiliations

¹ Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
² Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
³ Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA.
⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA.
⁵ Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁸ Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].
⁹ Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: [email protected].

Abstract

A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4⁺Foxp3^- T cells expressing PD-1 (4PD1^hi) and observed that 4PD1^hi accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1^hi increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1^hi reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1^hi inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (T_FH)-like cells. Accordingly, anti-CTLA-4 activity is improved in T_FH deficient mice.

Keywords: CD4(+) T cells; CTLA-4; PD-1; PD-L1; cancer immunotherapy; follicular helper T cells; immune checkpoint blockade; immune resistance; immune tolerance; regulatory T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / pharmacology
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
Cell Line, Tumor
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / immunology*
Forkhead Transcription Factors / metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / immunology
Humans
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / immunology*
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology*
Programmed Cell Death 1 Receptor / metabolism
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism

Substances

Antibodies
Forkhead Transcription Factors
Programmed Cell Death 1 Receptor

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States