To study the evolution of ICB resistance, Liu and Lin et al. performed an in-depth longitudinal analysis over 9 years with 37 samples of tumor, and microenvironmental evolution of a patient from diagnosis to rapid autopsy. Co-evolution of seven inferred lineages were present at therapy onset, each with distinct genomic features. Treatment-resistant lesions detected at autopsy arose from one lineage and were characterized by 15q deletion (ϐ3m), PTEN loss, genome doubling, and accumulation of driver mutations. Imaging revealed NGFRhi tumor cells with cytoarchitecture consistent with vascular mimicry, high PD-L1 expression, and hypoxia pathway enrichment.
Contributed by Shishir Pant
ABSTRACT: Despite initial responses(1-3), most melanoma patients develop resistance(4) to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR(hi) tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.
Author Info: (1) Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. (2) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, M
Author Info: (1) Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. (2) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. (3) Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. (4) Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (5) Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. (6) Broad Institute of Harvard and MIT, Cambridge, MA, USA. Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (8) Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA. Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Department of Pathology, Duke University School of Medicine, Durham, NC, USA. (9) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (10) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (11) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. (12) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. (13) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Broad Institute of Harvard and MIT, Cambridge, MA, USA. Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA. (15) Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. (16) Dana-Farber Cancer Institute, Boston, MA, USA. (17) Dana-Farber Cancer Institute, Boston, MA, USA. Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. (18) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (19) Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (20) Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. (21) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (22) Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (23) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (24) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (25) Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. (26) Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. (27) Broad Institute of Harvard and MIT, Cambridge, MA, USA. Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (28) Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. Department of Mathematics, Harvard University, Cambridge, MA, USA. (29) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (30) Department of Pathology, Harvard Medical School, Brigham and Woman's Hospital, Boston, MA, USA. (31) Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (32) Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA. Columbia Center for Translation Immunology, New York, NY, USA. (33) Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA. (34) Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. (35) Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Basser Center for BRCA, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (36) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (37) Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (38) Broad Institute of Harvard and MIT, Cambridge, MA, USA. Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA. (39) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Cambridge, MA, USA. (40) Broad Institute of Harvard and MIT, Cambridge, MA, USA. gmboland@mgh.harvard.edu. Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. gmboland@mgh.harvard.edu.
