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

Author:

Ricciuti Biagio1ORCID,Lamberti Giuseppe1ORCID,Puchala Sreekar R.2,Mahadevan Navin R.3ORCID,Lin Jia-Ren45,Alessi Joao V.1ORCID,Chowdhury Alexander2,Li Yvonne Y.26,Wang Xinan7,Spurr Liam6,Pecci Federica1,Di Federico Alessandro1ORCID,Venkatraman Deepti1,Barrichello Adriana P.1ORCID,Gandhi Malini1ORCID,Vaz Victor R.1,Pangilinan Andy J.1,Haradon Danielle1,Lee Elinton1,Gupta Hersh2ORCID,Pfaff Kathleen L.8ORCID,Welsh Emma L.8ORCID,Nishino Mizuki9ORCID,Cherniack Andrew D.25,Johnson Bruce E.1ORCID,Weirather Jason L8ORCID,Dryg Ian D8ORCID,Rodig Scott J.38,Sholl Lynette M.3ORCID,Sorger Peter345ORCID,Santagata Sandro345,Umeton Renato2ORCID,Awad Mark M.1ORCID

Affiliation:

1. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA

2. Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA

3. Department of Pathology, Brigham and Women's Hospital, Boston, MA

4. Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA

5. Ludwig Center at Harvard, Harvard Medical School, Boston, MA

6. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA

7. Harvard School of Public Health, Boston, MA

8. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA

9. Department of Radiology, Brigham and Women's Hospital, Boston, MA

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.

Publisher

American Society of Clinical Oncology (ASCO)

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