Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small-Cell Lung Cancer.

Autor:	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.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA., Alessi JV; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA., Chowdhury A; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA., Li YY; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA., Wang X; Harvard School of Public Health, Boston, MA., Spurr L; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA., Pecci F; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA., Di Federico A; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, 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; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA., Pfaff KL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA., Welsh EL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA., Nishino M; Department of Radiology, Brigham and Women's Hospital, Boston, MA., Cherniack AD; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA., Johnson BE; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA., Weirather JL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA., Dryg ID; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA., Rodig SJ; Department of Pathology, Brigham and Women's Hospital, Boston, MA.; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA., Sholl LM; Department of Pathology, Brigham and Women's Hospital, Boston, MA., Sorger P; Department of Pathology, Brigham and Women's Hospital, Boston, MA.; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA., Santagata S; Department of Pathology, Brigham and Women's Hospital, Boston, MA.; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA., Umeton R; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA., Awad MM; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2024 Apr 10; Vol. 42 (11), pp. 1311-1321. Date of Electronic Publication: 2024 Jan 11.
DOI:	10.1200/JCO.23.00580
Abstrakt:	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.
Databáze:	MEDLINE
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