Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses

Jennifer A. Lo; Masayoshi Kawakubo; Vikram R. Juneja; Mack Y. Su; Tal H. Erlich; Martin W. LaFleur; Lajos V. Kemeny; Mamunur Rashid; Mohsen Malehmir; S. Alireza Rabi; Rumya Raghavan; Jennifer Allouche; Gyulnara Kasumova; Dennie T. Frederick; Kristen E. Pauken; Qing Yu Weng; Marcelo Pereira da Silva; Yu Xu; Anita A. J. van der Sande; Whitney Silkworth; Elisabeth Roider; Edward P. Browne; David J. Lieb; Belinda Wang; Levi A. Garraway; Catherine J. Wu; Keith T. Flaherty; Constance E. Brinckerhoff; David W. Mullins; David J. Adams; Nir Hacohen; Mai P. Hoang; Genevieve M. Boland; Gordon J. Freeman; Arlene H. Sharpe; Dieter Manstein; David E. Fisher

doi:10.1126/scitranslmed.abd8636

Research ArticleCancer

Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses

View ORCID ProfileJennifer A. Lo¹,²,
Masayoshi Kawakubo¹,*,
Vikram R. Juneja³,⁴,*,
Mack Y. Su¹,²,*,
View ORCID ProfileTal H. Erlich¹,²,*,
View ORCID ProfileMartin W. LaFleur³,⁴,⁵,
View ORCID ProfileLajos V. Kemeny¹,²,
View ORCID ProfileMamunur Rashid⁶,
View ORCID ProfileMohsen Malehmir⁷,
S. Alireza Rabi⁷,
Rumya Raghavan⁸,⁹,
View ORCID ProfileJennifer Allouche¹,²,
Gyulnara Kasumova⁷,
Dennie T. Frederick⁷,
View ORCID ProfileKristen E. Pauken³,⁴,
View ORCID ProfileQing Yu Weng¹,²,
View ORCID ProfileMarcelo Pereira da Silva¹,
Yu Xu¹⁰,
Anita A. J. van der Sande¹,²,
View ORCID ProfileWhitney Silkworth¹,²,
Elisabeth Roider ¹,²,¹¹,¹²,¹³,
View ORCID ProfileEdward P. Browne¹⁴,
View ORCID ProfileDavid J. Lieb⁸,
View ORCID ProfileBelinda Wang⁸,¹⁵,
Levi A. Garraway⁸,¹⁵,
View ORCID ProfileCatherine J. Wu⁸,¹⁵,
View ORCID ProfileKeith T. Flaherty²,
Constance E. Brinckerhoff¹⁶,
David W. Mullins¹⁷,
David J. Adams⁶,
View ORCID ProfileNir Hacohen²,⁸,
View ORCID ProfileMai P. Hoang¹⁸,
View ORCID ProfileGenevieve M. Boland⁷,†,
View ORCID ProfileGordon J. Freeman ¹⁵,¹⁹,†,
View ORCID ProfileArlene H. Sharpe ³,⁴,⁸,†,
View ORCID ProfileDieter Manstein¹,† and
View ORCID ProfileDavid E. Fisher¹,²,†

¹Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
²Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
³Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
⁴Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA.
⁵Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
⁶Experimental Cancer Genetics, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
⁷Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹Harvard-MIT Health Sciences and Technology Program, Cambridge, MA 02139, USA.
¹⁰Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
¹¹Department of Dermatology and Allergology, University of Szeged, Szeged 6727, Hungary.
¹²Department of Dermatology, Venerology, and Allergology, Kantonsspital St. Gallen, St. Gallen 9000, Switzerland.
¹³University of Zurich, Zurich 8006, Switzerland.
¹⁴Department of Medicine, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁵Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁶Departments of Medicine and Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
¹⁷Departments of Medical Education and Microbiology/Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
¹⁸Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁹Harvard Medical School, Boston, MA 02115, USA.

↵†Corresponding author. Email: dfisher3{at}partners.org (D.E.F.); dmanstein{at}mgh.harvard.edu (D.M.); arlene_sharpe{at}hms.harvard.edu (A.H.S.); gordon_freeman{at}dfci.harvard.edu (G.J.F.); gmboland{at}partners.org (G.M.B.)

↵* These authors contributed equally to this work.

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Science Translational Medicine 17 Feb 2021:
Vol. 13, Issue 581, eabd8636
DOI: 10.1126/scitranslmed.abd8636

Jennifer A. Lo

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Masayoshi Kawakubo

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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Vikram R. Juneja

3Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.

4Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA.

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Mack Y. Su

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Tal H. Erlich

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Martin W. LaFleur

3Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.

4Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA.

5Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.

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Lajos V. Kemeny

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Mamunur Rashid

6Experimental Cancer Genetics, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

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Mohsen Malehmir

7Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

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S. Alireza Rabi

7Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

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Rumya Raghavan

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

9Harvard-MIT Health Sciences and Technology Program, Cambridge, MA 02139, USA.

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Jennifer Allouche

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Gyulnara Kasumova

7Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

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Dennie T. Frederick

7Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

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Kristen E. Pauken

3Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.

4Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA.

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Qing Yu Weng

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Marcelo Pereira da Silva

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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Yu Xu

10Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.

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Anita A. J. van der Sande

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Whitney Silkworth

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Elisabeth Roider

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

11Department of Dermatology and Allergology, University of Szeged, Szeged 6727, Hungary.

12Department of Dermatology, Venerology, and Allergology, Kantonsspital St. Gallen, St. Gallen 9000, Switzerland.

13University of Zurich, Zurich 8006, Switzerland.

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Edward P. Browne

14Department of Medicine, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.

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David J. Lieb

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Belinda Wang

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

15Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

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Levi A. Garraway

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

15Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

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Catherine J. Wu

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

15Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

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Keith T. Flaherty

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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Constance E. Brinckerhoff

16Departments of Medicine and Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.

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David W. Mullins

17Departments of Medical Education and Microbiology/Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.

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David J. Adams

6Experimental Cancer Genetics, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

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Nir Hacohen

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Mai P. Hoang

18Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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Genevieve M. Boland

7Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

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For correspondence: dfisher3@partners.org dmanstein@mgh.harvard.edu arlene_sharpe@hms.harvard.edu gordon_freeman@dfci.harvard.edu gmboland@partners.org

Gordon J. Freeman

15Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

19Harvard Medical School, Boston, MA 02115, USA.

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For correspondence: dfisher3@partners.org dmanstein@mgh.harvard.edu arlene_sharpe@hms.harvard.edu gordon_freeman@dfci.harvard.edu gmboland@partners.org

Arlene H. Sharpe

3Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.

4Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA.

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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For correspondence: dfisher3@partners.org dmanstein@mgh.harvard.edu arlene_sharpe@hms.harvard.edu gordon_freeman@dfci.harvard.edu gmboland@partners.org

Dieter Manstein

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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For correspondence: dfisher3@partners.org dmanstein@mgh.harvard.edu arlene_sharpe@hms.harvard.edu gordon_freeman@dfci.harvard.edu gmboland@partners.org

David E. Fisher

1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

2Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

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For correspondence: dfisher3@partners.org dmanstein@mgh.harvard.edu arlene_sharpe@hms.harvard.edu gordon_freeman@dfci.harvard.edu gmboland@partners.org

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Neoantigens sensitize melanomas to checkpoint blockade and trigger epitope spreading to self-antigens, a process mimicked by combination immunotherapy.

Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses

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