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Gregory J. Riely, MD, PhD


Understanding Acquired Resistance to Immunotherapy for NSCLC: Genomic and Immunophenotypic Insights

By: Julia Fiederlein Cipriano, MS
Posted: Friday, March 15, 2024

The results of a recent analysis, which were published in the Journal of Clinical Oncology, underscore the genomic and immunophenotypic heterogeneity of resistance to immune checkpoint inhibitors in non–small cell lung cancer (NSCLC). According to Mark M. Awad, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues, these data should be considered when developing novel therapeutic strategies aimed at overcoming such resistance. 

“Although immune checkpoint inhibitors have extended survival in patients with NSCLC, acquired resistance to immune checkpoint inhibitors frequently develops after an initial benefit,” the investigators commented. “[Prior to this analysis,] the mechanisms of acquired resistance to immune checkpoint inhibitors in NSCLC were largely unknown.”

The investigators performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with matched biopsies taken before and after immune checkpoint inhibition who developed acquired resistance to such therapy. Their findings were compared with those from two control cohorts that received intervening chemotherapy (n = 32) or targeted therapies (n = 89) between biopsies.

A total of 27.8% of the immunotherapy-treated cases exhibited putative resistance mutations, including acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2; these acquired alterations were not seen in the control cohorts. Based on immunophenotyping, matched samples taken before and after immune checkpoint inhibition demonstrated significant decreases in intratumoral lymphocytes, CD3e-positive and CD8a-positive T cells, and PD-L1–PD-1 engagement; the investigators also noted an increase in the distance between tumor cells and CD8-positive, PD-1–positive T cells. The level of human leukocyte antigen (HLA) class I expression was found to significantly decrease in the immunotherapy vs chemotherapy (P = .005) and targeted therapy (P = .01) cohorts at the time of acquired resistance.

Disclosure: For full disclosures of the study authors, visit

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