Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment

Autor: Etienne Becht, Susan Flynn, Michael G. Fehlings, Boon Heng Lee, Suchit Jhunjhunwala, Alessandra Nardin, Evan W. Newell, Marcin Kowanetz, William E. O'Gorman, Hermi Sumatoh, Marcus Ballinger, Priti S. Hegde, Mahesh Yadav
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
Cancer Research
Lung Neoplasms
T cell
medicine.medical_treatment
Immunology
Biology
CD8-Positive T-Lymphocytes
Major histocompatibility complex
Antibodies
Monoclonal
Humanized
NSCLC
lcsh:RC254-282
Epitope
B7-H1 Antigen
03 medical and health sciences
0302 clinical medicine
Immune system
Antineoplastic Agents
Immunological
Antigen
Antigens
Neoplasm
Carcinoma
Non-Small-Cell Lung
Exome Sequencing
medicine
Immunology and Allergy
Cytotoxic T cell
Humans
RNA-Seq
Atezolizumab
Aged
Pharmacology
integumentary system
Immunotherapy
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.anatomical_structure
Oncology
Tumor neoantigen-specific T cells
030220 oncology & carcinogenesis
Mutation
Cancer research
biology.protein
Molecular Medicine
Female
Drug Monitoring
CD8
030215 immunology
Research Article
Zdroj: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-15 (2019)
Journal for Immunotherapy of Cancer
ISSN: 2051-1426
0190-3993
DOI: 10.1186/s40425-019-0695-9
Popis: Background There is strong evidence that immunotherapy-mediated tumor rejection can be driven by tumor-specific CD8+ T cells reinvigorated to recognize neoantigens derived from tumor somatic mutations. Thus, the frequencies or characteristics of tumor-reactive, mutation-specific CD8+ T cells could be used as biomarkers of an anti-tumor response. However, such neoantigen-specific T cells are difficult to reliably identify due to their low frequency in peripheral blood and wide range of potential epitope specificities. Methods Peripheral blood mononuclear cells (PBMC) from 14 non-small cell lung cancer (NSCLC) patients were collected pre- and post-treatment with the anti-PD-L1 antibody atezolizumab. Using whole exome sequencing and RNA sequencing we identified tumor neoantigens that are predicted to bind to major histocompatibility complex class I (MHC-I) and utilized mass cytometry, together with cellular ‘barcoding’, to profile immune cells from patients with objective response to therapy (n = 8) and those with progressive disease (n = 6). In parallel, a highly-multiplexed combinatorial tetramer staining was used to screen antigen-specific CD8+ T cells in peripheral blood for 782 candidate tumor neoantigens and 71 known viral-derived control peptide epitopes across all patient samples. Results No significant treatment- or response associated phenotypic difference were measured in bulk CD8+ T cells. Multiplexed peptide-MHC multimer staining detected 20 different neoantigen-specific T cell populations, as well as T cells specific for viral control antigens. Not only were neoantigen-specific T cells more frequently detected in responding patients, their phenotypes were also almost entirely distinct. Neoantigen-specific T cells from responder patients typically showed a differentiated effector phenotype, most like Cytomegalovirus (CMV) and some types of Epstein-Barr virus (EBV)-specific CD8+ T cells. In contrast, more memory-like phenotypic profiles were observed for neoantigen-specific CD8+ T cells from patients with progressive disease. Conclusion This study demonstrates that neoantigen-specific T cells can be detected in peripheral blood in non-small cell lung cancer (NSCLC) patients during anti-PD-L1 therapy. Patients with an objective response had an enrichment of neoantigen-reactive T cells and these cells showed a phenotype that differed from patients without a response. These findings suggest the ex vivo identification, characterization, and longitudinal follow-up of rare tumor-specific differentiated effector neoantigen-specific T cells may be useful in predicting response to checkpoint blockade. Trial registration POPLAR trial NCT01903993. Electronic supplementary material The online version of this article (10.1186/s40425-019-0695-9) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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