Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy.

Autor:	Reinstein ZZ; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Zhang Y; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Ospina OE; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Nichols MD; Department of Tumor Metastasis and Microenvironment, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Chu VA; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Pulido AM; Department of Tumor Metastasis and Microenvironment, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Prieto K; Department of Tumor Metastasis and Microenvironment, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Nguyen JV; Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Yin R; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland., Moran Segura C; Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Usman A; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Sell B; Department of Tumor Metastasis and Microenvironment, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Ng S; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois., de la Iglesia JV; Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Chandra S; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Sosman JA; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Cho RJ; Department of Dermatology, University of California, San Francisco, San Francisco, California., Cheng JB; Department of Dermatology, University of California, San Francisco, San Francisco, California.; Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California., Ivanova E; Department of Pathology, New York University School of Medicine, New York, New York., Koralov SB; Department of Pathology, New York University School of Medicine, New York, New York.; Kimmel Center for Biology and Medicine at the Skirball Institute, New York University, Grossman School of Medicine, New York, New York., Slebos RJC; Department of Head and Neck Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Chung CH; Department of Head and Neck Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Khushalani NI; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Donald A. Adam Melanoma and Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Messina JL; Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Donald A. Adam Melanoma and Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Sarnaik AA; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Donald A. Adam Melanoma and Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Zager JS; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Donald A. Adam Melanoma and Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Sondak VK; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Donald A. Adam Melanoma and Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Vaske C; Clear Labs, Santa Cruz, California., Kim S; Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Brohl AS; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Donald A. Adam Melanoma and Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Mi X; Department of Preventive Medicine-Biostatistics Quantitative Data Sciences Core, Northwestern University, Chicago, Illinois., Pierce BG; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland.; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland., Wang X; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Fridley BL; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Tsai KY; Department of Tumor Metastasis and Microenvironment, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Donald A. Adam Melanoma and Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Choi J; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.; Center for Synthetic Biology, Northwestern University, Evanston, Illinois.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Sep 04; Vol. 14 (9), pp. 1631-1652.
DOI:	10.1158/2159-8290.CD-23-0798
Abstrakt:	Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ∼50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (RNA-seq) with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1. Responders have increased type I/II interferons and preexisting tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public T-cell receptors. Spatial transcriptomics demonstrated colocalization of T cells with B and dendritic cells, which supply chemokines and costimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC. Significance: MCC serves as a model of ICB response. We utilized the largest-to-date, multimodal MCC dataset (n = 116 patients) to uncover unique tumor-intrinsic properties and immune circuits that predict response. We identified CD8 Trm and Vδ1 T cells as clinically actionable mediators of ICB response in major histocompatibility complex-high and -low MCCs, respectively. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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