Study uncovers mechanisms of resistance to immunotherapy in metastatic non-small cell lung cancer

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

Publication: Journal of Clinical Oncology

Dana-Farber Cancer Institute author: Biagio Ricciuti, MD, PhD, Giuseppe Lamberti, MD, Mark M. Awad, MD, PhD

Summary: Patients with metastatic non-small cell lung cancer (NSCLC) who respond to treatment with immune checkpoint inhibitor immunotherapy eventually relapse. A new study by Dana-Farber Cancer Institute researchers provides a detailed assessment of how NSCLC tumors acquire resistance to immunotherapy. The researchers examined biopsies of NSCLC tumors before and after treatment with anti-PD-(L)1 immune checkpoint inhibitor therapy. Among tumors that had acquired resistance and progressed during treatment, the team identified alterations in a range of genes, including loss-of-function mutations in genes, such as STK11, KEAP1, B2M, JAK1, and losses in functionality of genes encoding PD-L1 and PD-L2. They also noted a decrease in the density of tumor infiltrating leukocytes, which include immune cells, such as T cells that fight cancer. Further, they observed a decrease in the presentation of antigens, measured as a decrease in HLA class 1 expression, that instigate immune responses. The genetic alterations and immunologic changes observed in samples associated with resistance to immune checkpoint inhibitors were distinct from those observed in controls, which included samples from patients who had received chemotherapy or targeted therapy and progressed between biopsies.
Impact: NSCLC tumors change in various ways to evade immunotherapy. Some of the alterations create vulnerabilities that could be targeted by existing approved therapies. These results can inform the rational development of novel and personalized therapeutic strategies to overcome, prevent, and possibly delay acquired resistance to immunotherapy.

Funding: The Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research, LUNGSTRONG, the Barbara Wilson Gomez Endowed Fellowship in Thoracic Oncology, the Society for Immunotherapy of Cancer Astra-Zeneca Lung Cancer Clinical Fellowship.