Wang et al. performed multidimensional analysis on longitudinal tumor and blood samples in a clinical trial of TIL therapy in 16 patients with metastatic NSCLC. In patients that did not clinically benefit, tumor neoantigen-reactive clonotypes were less cytolytic, expressed a dysfunctional program, and lacked stem/memory-like self-renewal. Further, loss of infused cells or of neoantigen-reactive peripheral T cell clonotypes over time was associated with the onset of progressive disease. Subclonal neoantigens that were previously targeted by infused TILs were absent from tumor cell genomes upon progression, suggesting adaptive resistance.
Contributed by Lauren Hitchings
ABSTRACT: Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. chao.wang@moffitt.org. (2) Department of Biostatistics and Bioinformatics, H. Lee M
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. chao.wang@moffitt.org. (2) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (3) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (5) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (6) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (7) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (8) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (9) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (10) Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. (11) Center for Immunotherapy and Precision Immuno-oncology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA. (12) Center for Immunotherapy and Precision Immuno-oncology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA. (13) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. Department of Integrative Immunobiology, Duke School of Medicine, Durham, NC, USA. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA. (14) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (15) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (16) Proteomics & Metabolomics Core Facility, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (17) Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (18) Immune and Cellular Therapy Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (19) Immune and Cellular Therapy Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (20) Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (21) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. Department of Radiation Oncology, Immunology, Cancer Biology, Mayo Clinic Alix College of Medicine & Health Sciences, Jacksonville, FL, USA. (22) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (23) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (24) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. Department of Integrative Immunobiology, Duke School of Medicine, Durham, NC, USA. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA. (25) Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA. (26) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (27) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. ben.creelan@moffitt.org. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. ben.creelan@moffitt.org.
