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Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies.

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Title: Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies.
Authors: Shamin Lia1 shaminli@fredhutch.org, Simoni, Yannick1,2, Zhuang, Summer1, Gabel, Austin3,4,5,6, Shaokang Ma7, Chee, Jonathan7, Islas, Laura1, Cessna, Anthony1, Creaney, Jenette7,8,9, Bradley, Robert K.3,4,5, Redwood, Alec7, Robinson, Bruce W.7, Newell, Evan W.1 enewell@fredhutch.org
Source: Proceedings of the National Academy of Sciences of the United States of America. 7/27/2021, Vol. 118 Issue 30, p1-10. 10p.
Subjects: Immune checkpoint proteins, T cells, Cancer cells, Major histocompatibility complex
Abstract: Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti-PD-1 and anti-CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen-specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigenspecific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies.
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  Data: <searchLink fieldCode="AR" term="%22Shamin+Lia%22">Shamin Lia</searchLink><relatesTo>1</relatesTo><i> shaminli@fredhutch.org</i><br /><searchLink fieldCode="AR" term="%22Simoni%2C+Yannick%22">Simoni, Yannick</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Zhuang%2C+Summer%22">Zhuang, Summer</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Gabel%2C+Austin%22">Gabel, Austin</searchLink><relatesTo>3,4,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Shaokang+Ma%22">Shaokang Ma</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Chee%2C+Jonathan%22">Chee, Jonathan</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Islas%2C+Laura%22">Islas, Laura</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Cessna%2C+Anthony%22">Cessna, Anthony</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Creaney%2C+Jenette%22">Creaney, Jenette</searchLink><relatesTo>7,8,9</relatesTo><br /><searchLink fieldCode="AR" term="%22Bradley%2C+Robert+K%2E%22">Bradley, Robert K.</searchLink><relatesTo>3,4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Redwood%2C+Alec%22">Redwood, Alec</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Robinson%2C+Bruce+W%2E%22">Robinson, Bruce W.</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Newell%2C+Evan+W%2E%22">Newell, Evan W.</searchLink><relatesTo>1</relatesTo><i> enewell@fredhutch.org</i>
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  Data: Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti-PD-1 and anti-CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen-specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigenspecific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2025570118
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        Text: English
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      – SubjectFull: Immune checkpoint proteins
        Type: general
      – SubjectFull: T cells
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      – SubjectFull: Cancer cells
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