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CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load and TP53 mutations

Andrew M. Leader, John A. Grout, Christie Chang, Barbara Maier, Alexandra Tabachnikova, Laura Walker, Alona Lansky, Jessica LeBerichel, Naussica Malissen, Melanie Davila, Jerome Martin, Giuliana Magri, Kevin Tuballes, Zhen Zhao, Francesca Petralia, Robert Samstein, Natalie Roy D’Amore, Gavin Thurston, Alice Kamphorst, Andrea Wolf, Raja Flores, Pei Wang, Mary Beth Beasley, Helene Salmon, Adeeb H. Rahman, Thomas U. Marron, Ephraim Kenigsberg, Miriam Merad
doi: https://doi.org/10.1101/2020.07.16.207605
Andrew M. Leader
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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John A. Grout
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Christie Chang
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Barbara Maier
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Alexandra Tabachnikova
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Laura Walker
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Alona Lansky
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Jessica LeBerichel
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Naussica Malissen
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Melanie Davila
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Jerome Martin
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
5Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, F-44000 Nantes, France ; CHU Nantes, Nantes Université, Laboratoire d’Immunologie, F-44000 Nantes, France
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Giuliana Magri
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Kevin Tuballes
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Zhen Zhao
6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Francesca Petralia
7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
8Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Robert Samstein
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
9Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Natalie Roy D’Amore
10Immuno-oncology Drug Discovery Unit, Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tarrytown, NY, 10591, USA
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Gavin Thurston
11Department of Oncology & Angiogenesis, Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10591, USA
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Alice Kamphorst
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Andrea Wolf
12Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Raja Flores
12Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Pei Wang
7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
8Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Mary Beth Beasley
6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Helene Salmon
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Adeeb H. Rahman
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Thomas U. Marron
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
13Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Ephraim Kenigsberg
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
8Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • For correspondence: miriam.merad@mssm.edu ephraim.kenigsberg@mssm.edu
Miriam Merad
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • For correspondence: miriam.merad@mssm.edu ephraim.kenigsberg@mssm.edu
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SUMMARY

Immunotherapy is becoming a mainstay in the treatment of NSCLC. While tumor mutational burden (TMB) has been shown to correlate with response to immunotherapy, little is known about the relation of the baseline immune response with the tumor genotype. Here, we profiled 35 early stage NSCLC lesions using multiscale single cell sequencing. Unsupervised clustering identified in a subset of patients a key cellular module consisting of PDCD1+ CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). Transcriptional data from two NSCLC cohorts confirmed a subset of patients with LCAMhi enrichment, which was independent of overall immune cell content. The LCAMhi module strongly correlated with TMB, expression of cancer testis antigens, and with TP53 mutations in smokers and non-smokers. These data establish LCAM as a key mode of immune cell activation associated with high tumor antigen load and driver mutations.

Competing Interest Statement

Research support for this work was provided by Regeneron and Takeda. The authors declare no other competing financial interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 17, 2020.
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CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load and TP53 mutations
Andrew M. Leader, John A. Grout, Christie Chang, Barbara Maier, Alexandra Tabachnikova, Laura Walker, Alona Lansky, Jessica LeBerichel, Naussica Malissen, Melanie Davila, Jerome Martin, Giuliana Magri, Kevin Tuballes, Zhen Zhao, Francesca Petralia, Robert Samstein, Natalie Roy D’Amore, Gavin Thurston, Alice Kamphorst, Andrea Wolf, Raja Flores, Pei Wang, Mary Beth Beasley, Helene Salmon, Adeeb H. Rahman, Thomas U. Marron, Ephraim Kenigsberg, Miriam Merad
bioRxiv 2020.07.16.207605; doi: https://doi.org/10.1101/2020.07.16.207605
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CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load and TP53 mutations
Andrew M. Leader, John A. Grout, Christie Chang, Barbara Maier, Alexandra Tabachnikova, Laura Walker, Alona Lansky, Jessica LeBerichel, Naussica Malissen, Melanie Davila, Jerome Martin, Giuliana Magri, Kevin Tuballes, Zhen Zhao, Francesca Petralia, Robert Samstein, Natalie Roy D’Amore, Gavin Thurston, Alice Kamphorst, Andrea Wolf, Raja Flores, Pei Wang, Mary Beth Beasley, Helene Salmon, Adeeb H. Rahman, Thomas U. Marron, Ephraim Kenigsberg, Miriam Merad
bioRxiv 2020.07.16.207605; doi: https://doi.org/10.1101/2020.07.16.207605

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