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The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution

View ORCID ProfileAjit J. Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce A. Chen, Connor A. Jacobson, Roxanne J. Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine G. Lian, George F. Murphy, View ORCID ProfileSandro Santagata, View ORCID ProfilePeter K. Sorger
doi: https://doi.org/10.1101/2021.05.23.445310
Ajit J. Nirmal
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
3Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
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  • ORCID record for Ajit J. Nirmal
Zoltan Maliga
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
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Tuulia Vallius
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
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Brian Quattrochi
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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Alyce A. Chen
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
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Connor A. Jacobson
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
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Roxanne J. Pelletier
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
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Clarence Yapp
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
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Raquel Arias-Camison
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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Yu-An Chen
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
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Christine G. Lian
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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George F. Murphy
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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Sandro Santagata
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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  • For correspondence: peter_sorger@hms.harvard.edu sorger_admin@hms.harvard.edu
Peter K. Sorger
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2Ludwig Center at Harvard, Boston, MA, 02115, USA.
5Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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  • For correspondence: peter_sorger@hms.harvard.edu sorger_admin@hms.harvard.edu
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ABSTRACT

Cutaneous melanoma is a highly immunogenic malignancy, surgically curable at early stages, but life- threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1-PDL1 mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can co-exist within a few millimeters of each other in a single specimen.

STATEMENT OF SIGNIFICANCE The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classical histopathology, spatial profiling of proteins and mRNA reveals recurrent morphological and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell-cell contact.

Competing Interest Statement

PKS is a member of the SAB or Board of Directors of Glencoe Software, Applied Biomath, and RareCyte Inc. and has equity in these companies; PKS is also a member of the SAB of NanoString and a consultant for Montai Health and Merck. Glencoe, RareCyte, and NanoString provided commercially-available technology used in this study. SS is a consultant for RareCyte Inc. ZM is a consultant for Verseau Therapeutics Inc. The authors declare that none of these relationships have influenced the content of this manuscript.

Footnotes

  • Human Tumor Atlas Network

  • https://labsyspharm.github.io/HTA-MELATLAS-1/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 14, 2022.
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The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution
Ajit J. Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce A. Chen, Connor A. Jacobson, Roxanne J. Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine G. Lian, George F. Murphy, Sandro Santagata, Peter K. Sorger
bioRxiv 2021.05.23.445310; doi: https://doi.org/10.1101/2021.05.23.445310
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The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution
Ajit J. Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce A. Chen, Connor A. Jacobson, Roxanne J. Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine G. Lian, George F. Murphy, Sandro Santagata, Peter K. Sorger
bioRxiv 2021.05.23.445310; doi: https://doi.org/10.1101/2021.05.23.445310

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