Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy

Tuba N Gide; Camelia Quek; Alexander M Menzies; Annie T Tasker; Ping Shang; Jeff Holst; Jason Madore; Su Yin Lim; Rebecca Velickovic; Matthew Wongchenko; Yibing Yan; Serigne Lo; Matteo S Carlino; Alexander Guminski; Robyn P M Saw; Angel Pang; Helen M McGuire; Umaimainthan Palendira; John F Thompson; Helen Rizos; Ines Pires da Silva; Marcel Batten; Richard A Scolyer; Georgina V Long; James S Wilmott

doi:10.1016/j.ccell.2019.01.003

Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy

Cancer Cell. 2019 Feb 11;35(2):238-255.e6. doi: 10.1016/j.ccell.2019.01.003.

Authors

Tuba N Gide¹, Camelia Quek¹, Alexander M Menzies², Annie T Tasker³, Ping Shang³, Jeff Holst⁴, Jason Madore³, Su Yin Lim⁵, Rebecca Velickovic³, Matthew Wongchenko⁶, Yibing Yan⁶, Serigne Lo³, Matteo S Carlino⁷, Alexander Guminski², Robyn P M Saw⁸, Angel Pang⁴, Helen M McGuire⁹, Umaimainthan Palendira⁴, John F Thompson⁸, Helen Rizos⁵, Ines Pires da Silva¹, Marcel Batten¹, Richard A Scolyer⁸, Georgina V Long², James S Wilmott¹⁰

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
² Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Department of Medical Oncology, Mater Hospital, North Sydney, NSW 2060, Australia.
³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia.
⁴ Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
⁶ Oncology Biomarker Development, Genentech Inc, South San Francisco, CA 94080, USA.
⁷ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW 2145, Australia.
⁸ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.
⁹ Ramaciotti Facility for Human Systems Biology, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
¹⁰ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: james.wilmott@melanoma.org.au.

PMID: 30753825
DOI: 10.1016/j.ccell.2019.01.003

Abstract

Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments. Further mass cytometry analysis identified an EOMES⁺CD69⁺CD45RO⁺ effector memory T cell phenotype that was significantly more abundant in responders to combined immunotherapy compared with non-responders (n = 18). The gene expression profile of this population was associated with longer progression-free survival in patients treated with single agent and greater tumor shrinkage in both treatments.

Keywords: EOMES; RNA-seq; anti-CTLA-4; anti-PD-1; combination therapy; immune checkpoint inhibitors; immunotherapy; melanoma; predictive biomarkers; resistance mechanisms.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antibodies, Monoclonal, Humanized / administration & dosage*
Antigens, CD / immunology
Antigens, Differentiation, T-Lymphocyte / immunology
Antineoplastic Agents, Immunological / administration & dosage*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
CTLA-4 Antigen / antagonists & inhibitors*
CTLA-4 Antigen / immunology
Drug Resistance, Neoplasm
Female
Humans
Immunologic Memory / drug effects
Ipilimumab / administration & dosage*
Lectins, C-Type / immunology
Leukocyte Common Antigens / immunology
Lymphocytes, Tumor-Infiltrating / drug effects*
Lymphocytes, Tumor-Infiltrating / immunology
Male
Melanoma / drug therapy*
Melanoma / genetics
Melanoma / immunology
Melanoma / pathology
Middle Aged
Nivolumab / administration & dosage*
Phenotype
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Programmed Cell Death 1 Receptor / immunology
Retrospective Studies
Signal Transduction / drug effects
Skin Neoplasms / drug therapy*
Skin Neoplasms / genetics
Skin Neoplasms / immunology
Skin Neoplasms / pathology
T-Lymphocytes / drug effects*
T-Lymphocytes / immunology
Treatment Outcome
Tumor Burden / drug effects

Substances

Antibodies, Monoclonal, Humanized
Antigens, CD
Antigens, Differentiation, T-Lymphocyte
Antineoplastic Agents, Immunological
CD69 antigen
CTLA-4 Antigen
CTLA4 protein, human
Ipilimumab
Lectins, C-Type
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Nivolumab
pembrolizumab
Leukocyte Common Antigens