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Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small-Cell Lung Cancer.
Ricciuti, Biagio; Lamberti, Giuseppe; Puchala, Sreekar R; Mahadevan, Navin R; Lin, Jia-Ren; Alessi, Joao V; Chowdhury, Alexander; Li, Yvonne Y; Wang, Xinan; Spurr, Liam; Pecci, Federica; Di Federico, Alessandro; Venkatraman, Deepti; Barrichello, Adriana P; Gandhi, Malini; Vaz, Victor R; Pangilinan, Andy J; Haradon, Danielle; Lee, Elinton; Gupta, Hersh; Pfaff, Kathleen L; Welsh, Emma L; Nishino, Mizuki; Cherniack, Andrew D; Johnson, Bruce E; Weirather, Jason L; Dryg, Ian D; Rodig, Scott J; Sholl, Lynette M; Sorger, Peter; Santagata, Sandro; Umeton, Renato; Awad, Mark M.
Afiliación
  • Ricciuti B; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Lamberti G; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Puchala SR; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA.
  • Mahadevan NR; Department of Pathology, Brigham and Women's Hospital, Boston, MA.
  • Lin JR; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA.
  • Alessi JV; Ludwig Center at Harvard, Harvard Medical School, Boston, MA.
  • Chowdhury A; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Li YY; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA.
  • Wang X; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA.
  • Spurr L; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA.
  • Pecci F; Harvard School of Public Health, Boston, MA.
  • Di Federico A; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA.
  • Venkatraman D; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Barrichello AP; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Gandhi M; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Vaz VR; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Pangilinan AJ; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Haradon D; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Lee E; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Gupta H; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Pfaff KL; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Welsh EL; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA.
  • Nishino M; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Cherniack AD; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Johnson BE; Department of Radiology, Brigham and Women's Hospital, Boston, MA.
  • Weirather JL; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA.
  • Dryg ID; Ludwig Center at Harvard, Harvard Medical School, Boston, MA.
  • Rodig SJ; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Sholl LM; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Sorger P; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Santagata S; Department of Pathology, Brigham and Women's Hospital, Boston, MA.
  • Umeton R; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Awad MM; Department of Pathology, Brigham and Women's Hospital, Boston, MA.
J Clin Oncol ; 42(11): 1311-1321, 2024 Apr 10.
Article en En | MEDLINE | ID: mdl-38207230
ABSTRACT

PURPOSE:

Although immune checkpoint inhibitors (ICI) have extended survival in patients with non-small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown.

METHODS:

Comprehensive tumor genomic profiling, machine learning-based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls.

RESULTS:

We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e+ and CD8a+ T cells, and PD-L1-PD1 engagement, as well as increased distance between tumor cells and CD8+PD-1+ T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy (P = .005) and the targeted therapy (P = .01) cohorts.

CONCLUSION:

These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Antineoplásicos Inmunológicos / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Clin Oncol Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Antineoplásicos Inmunológicos / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Clin Oncol Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos