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

• Published in: Cancer cell 2019-02, Vol.35 (2), p.238-255.e6
• Main Authors: Gide, Tuba N., Quek, Camelia, Menzies, Alexander M., Tasker, Annie T., Shang, Ping, Holst, Jeff, Madore, Jason, Lim, Su Yin, Velickovic, Rebecca, Wongchenko, Matthew, Yan, Yibing, Lo, Serigne, Carlino, Matteo S., Guminski, Alexander, Saw, Robyn P.M., Pang, Angel, McGuire, Helen M., Palendira, Umaimainthan, Thompson, John F., Rizos, Helen, Silva, Ines Pires da, Batten, Marcel, Scolyer, Richard A., Long, Georgina V., Wilmott, James S.
• Format: Article
• Language: English
• Subjects: Aged; anti-CTLA-4; anti-PD-1; Antibodies, Monoclonal, Humanized - administration & dosage; Antigens, CD - immunology; Antigens, Differentiation, T-Lymphocyte - immunology; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; combination therapy; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; Drug Resistance, Neoplasm; EOMES; Female; Humans; immune checkpoint inhibitors; Immunologic Memory - drug effects; immunotherapy; Ipilimumab - administration & dosage; Lectins, C-Type - immunology; Leukocyte Common Antigens - immunology; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Male; melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; Middle Aged; Nivolumab - administration & dosage; Phenotype; predictive biomarkers; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; resistance mechanisms; Retrospective Studies; RNA-seq; 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
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2019.01.003

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. [Display omitted] •Activated T cell signatures/populations drive response to anti-PD-1-based therapies•EOMES+CD69+CD45RO+ effector memory T cells are associated with response•EOMES+CD69+CD45RO+ expression is associated with longer PFS and tumor shrinkage•Non-responders with TIL-hot tumors express other immune drug targets Gide et al. characterize melanoma samples from patients treated with anti-PD-1 alone or with anti-CTLA-4. Tumors from non-responders to monotherapy often express other immune checkpoints and higher gene expression profile of EOMES+CD69+CD45RO+ T cells is associated with greater tumor shrinkage in both therapies.