한빛사논문
- 조회379
Hee-Jin Jang1, Hyun-Sung Lee1, Wendong Yu2, Maheshwari Ramineni3, Cynthia Y. Truong1, Daniela Ramos1, Taylor Splawn1, Jong Min Choi1, Sung Yun Jung4, Ju-Seog Lee5, Daniel Y. Wang6, Joel M. Sederstrom7, Massimo Pietropaolo8, Farrah Kheradmand9,10, Christopher I. Amos11, Thomas M. Wheeler3, R. Taylor Ripley12, and Bryan M. Burt1
1Systems Onco-Immunology Laboratory, The David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
2Department of Pathology/Laboratory Medicine, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
4Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas.
5Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6Division of Hemato-Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
7Advanced Technology Cores, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
8Division of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
9Division of Pulmonology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
10Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Department of Veterans Affairs, Houston, Texas.
11Dan L Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas.
12The David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
H.-J. Jang and H.-S. Lee contributed equally as co-first authors of this article.
H.-S. Lee and B.M. Burt contributed equally as corresponding authors.
Corresponding Authors: Hyun-Sung Lee, Bryan M. Burt.
Abstract
Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here, we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of preinvasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, complementary capabilities of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry was leveraged to identify cellular and spatial immune contextures in LUAD. Comprehensive investigation of mouse and human LUAD using these single-cell proteomics platforms showed that LUAD progression is associated with spatiotemporal evolution of tumor-associated macrophages in the tumor-immune microenvironment, which governs tumor response to immunotherapy. PD-1 was expressed in a highly plastic tumor-promoting subtype of tumor-associated macrophages that develops during tumor progression from preinvasive to invasive adenocarcinoma, controls the lymphocyte-depleted niche of invasive tumors, and protects tumor cells in the solid histologic components of the tumor. Longitudinal, multidimensional single-cell analyses of LUAD tumorigenesis revealed dynamic alteration of immunoregulatory PD-1–expressing tumor-associated macrophages that can be targeted to overcome resistance to checkpoint immunotherapy.
논문정보
- Research article
- 2022년 07월 (BRIC 등록일 2022-09-08)
- 국외 연구진
- 의약학 > 응용의학
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