Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma
Year: 2020
Type: article
Abstract: Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
Source: Nature Communications
Authors: Akash Mitra, Miles C. Andrews, Whijae Roh, Marianna Petaccia De Macedo, Courtney W. Hudgens, Fernando Carapeto, Shailbala Singh, Alexandre Reuben, Feng Wang, Xizeng Mao, Xingzhi Song, Khalida Wani, Samantha Tippen, Kwok-Shing Ng, Aislyn Schalck, Donald A. Sakellariou-Thompson, Eveline Chen, Sangeetha M. Reddy, Christine N. Spencer, Diana Wiesnoski, Latasha D. Little, Curtis Gumbs, Zachary A. Cooper, Elizabeth M. Burton, Patrick Hwu, Michael A. Davies, Jianhua Zhang, Chantale Bernatchez, Nicholas Navin, Padmanee Sharma, James P. Allison, Jennifer A. Wargo, Cassian Yee, Michael T. Tetzlaff, Wen-Jen Hwu, Alexander J. Lazar, P. Andrew Futreal
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: Amgen, Bristol-Myers Squibb, AstraZeneca, GlaxoSmithKline, Sanofi, Cancer Prevention and Research Institute of Texas, Gilead Sciences, Parker Institute for Cancer Immunotherapy, Myriad Genetics, Astellas Pharma, National Institutes of Health, Genentech, EMD Serono, University of Texas MD Anderson Cancer Center, Merck Sharp and Dohme, Kite Pharma, Medical Research Council, National Health and Medical Research Council, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G10598100, G111615301, The Future of Cancer Research: Training Program for Basic and Translational Scientists, G132965223, Deriving actionable strategies to enhance cancer immunotherapy response, G1619438925, G4932020558, Recruitment of Established Investigators, Cancer Center Support Grant, Comprehensive Musculoskeletal Training Program
OpenAlex ID: W3016947983