Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer

Stephen L Shiao¹, Kenneth H Gouin 3rd², Nathan Ing², Alice Ho³, Reva Basho⁴, Aagam Shah², Richard H Mebane², David Zitser², Andrew Martinez², Natalie-Ya Mevises⁵, Bassem Ben-Cheikh², Regina Henson⁵, Monica Mita⁶, Philomena McAndrew⁶, Scott Karlan⁷, Armando Giuliano⁷, Alice Chung⁷, Farin Amersi⁷, Catherine Dang⁷, Heather Richardson⁷, Wonwoo Shon⁸, Farnaz Dadmanesh⁸, Michele Burnison⁵, Amin Mirhadi⁵, Zachary S Zumsteg⁹, Rachel Choi⁵, Madison Davis⁵, Joseph Lee⁵, Dustin Rollins², Cynthia Martin⁵, Negin H Khameneh⁵, Heather McArthur¹⁰, Simon R V Knott¹¹

Affiliations

¹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: stephen.shiao@cshs.org.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Breast Cancer Clinical Research Unit, Duke University Medical Center, Raleigh, NC, USA. Electronic address: alice.ho@duke.edu.
⁴ Ellison Institute of Technology, Los Angeles, CA, USA.
⁵ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Department of Medicine, Division of Hematology-Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰ Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: heather.mcarthur@utsouthwestern.edu.
¹¹ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: simon.knott@cshs.org.

PMID: 38194915
DOI: 10.1016/j.ccell.2023.12.012

Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer

Stephen L Shiao et al. Cancer Cell. 2024.

. 2024 Jan 8;42(1):70-84.e8.

doi: 10.1016/j.ccell.2023.12.012.

Authors

Affiliations

¹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: stephen.shiao@cshs.org.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Breast Cancer Clinical Research Unit, Duke University Medical Center, Raleigh, NC, USA. Electronic address: alice.ho@duke.edu.
⁴ Ellison Institute of Technology, Los Angeles, CA, USA.
⁵ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Department of Medicine, Division of Hematology-Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰ Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: heather.mcarthur@utsouthwestern.edu.
¹¹ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: simon.knott@cshs.org.

PMID: 38194915
DOI: 10.1016/j.ccell.2023.12.012

Abstract

Strategies are needed to better identify patients that will benefit from immunotherapy alone or who may require additional therapies like chemotherapy or radiotherapy to overcome resistance. Here we employ single-cell transcriptomics and spatial proteomics to profile triple negative breast cancer biopsies taken at baseline, after one cycle of pembrolizumab, and after a second cycle of pembrolizumab given with radiotherapy. Non-responders lack immune infiltrate before and after therapy and exhibit minimal therapy-induced immune changes. Responding tumors form two groups that are distinguishable by a classifier prior to therapy, with one showing high major histocompatibility complex expression, evidence of tertiary lymphoid structures, and displaying anti-tumor immunity before treatment. The other responder group resembles non-responders at baseline and mounts a maximal immune response, characterized by cytotoxic T cell and antigen presenting myeloid cell interactions, only after combination therapy, which is mirrored in a murine model of triple negative breast cancer.

Keywords: Breast cancer metastasis; CAR T cell; T cell; TCR T cell; disseminated tumor cells; immunotherapy; tumor dormancy; tumor microenvironment; vaccine.

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Conflict of interest statement

Declaration of interests H.L.M. has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune. H.L.M. has received research support from Bristol-Myers Squibb; MedImmune, LLC/AstraZeneca; BTG; and Merck. R.B. has received research support (to the institution) from Genentech, AstraZeneca, Merck, Takeda, Eli Lilly, Pfizer, and Seattle Genetics, has received consulting fees from Pfizer, AstraZeneca, Seattle Genetics, and Gilead, and has received compensation to serve as a speaker/panelist for MJH Healthcare, Eli Lilly, and Curio Science. S.L.S. has received project-based research funding from Merck outside of the submitted work. S.R.V.K. is a founder and consultant at Faeth Therapeutics and Transomic Technologies. None of these disclosures are related to this work. No other potential disclosures are reported by any of the authors.

Comment in

Neoadjuvant radioimmunotherapy synergy in triple-negative breast cancer: Is microenvironment-guided patient selection on the horizon?
Shaitelman SF, Woodward WA. Shaitelman SF, et al. Cancer Cell. 2024 Jan 8;42(1):10-12. doi: 10.1016/j.ccell.2023.12.009. Cancer Cell. 2024. PMID: 38194911

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Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer

Affiliations

Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Publication types

MeSH terms

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Grants and funding