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

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          Abstract

          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.

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          Most cited references16

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          Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing.

          Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self' neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the >1,300 amino acid changes identified, ∼13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.
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            Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors

            Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies.
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              Visualizing data using ti-SNE

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                Author and article information

                Contributors
                michael.fehlings@immunoscape.com
                jhunjhunwala.suchit@gene.com
                marcinkowanetz@gmail.com
                ogormanw@gene.com
                hegde.priti@gene.com
                hermi.sumatoh@immunoscape.com
                boonheng.lee@immunoscape.com
                alessandra.nardin@lmmunoscape.com
                ebecht@fredhutch.org
                flynn.susan@gene.com
                ballinger.marcus@gene.com
                enewell@fredhutch.org
                yadav.mahesh@gene.com
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                12 September 2019
                12 September 2019
                2019
                : 7
                : 249
                Affiliations
                [1 ]ISNI 0000 0004 0534 4718, GRID grid.418158.1, Genentech, 1 DNA way, ; South San Francisco, CA 94080 USA
                [2 ]immunoSCAPE Pte Ltd, Singapore, Singapore
                [3 ]ISNI 0000 0004 0387 2429, GRID grid.430276.4, Agency for Science, Technology and Research (A*STAR), , Singapore Immunology Network (SIgN), ; Singapore, Singapore
                Article
                695
                10.1186/s40425-019-0695-9
                6740011
                31511069
                978f53f5-feaf-4ffd-ae6c-8bca28cab4fc
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 April 2019
                : 25 July 2019
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                immunotherapy,atezolizumab,nsclc,tumor neoantigen-specific t cells

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