The addition of radiation may be able to surmount resistance to immunotherapy for some more immunologically “cold” tumors, as suggested by the findings of a study focused on the immunomodulatory effects of radiation in non–small cell lung cancers (NSCLCs). The research was recently published in Nature Cancer.
“For a fraction of lung cancers where we aren’t expecting therapy responses, radiation may be particularly effective to help circumvent primary resistance to immunotherapy; this could potentially be applicable to acquired resistance, too,” stated senior study author Valsamo Anagnostou, MD, PhD, Co-Director of the Upper Aerodigestive Malignancies Program, Director of the Thoracic Oncology Biorepository, Leader of Precision Oncology Analytics, Co-Leader of the Johns Hopkins Molecular Tumor Board, and Co-Director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins Kimmel Cancer Center Bloomberg–Kimmel Institute for Cancer Immunotherapy.
Study Methods and Rationale
Many investigators have tried to understand what makes some tumors resistant to immunotherapy and how such resistance may be overcome. Radiation therapy is one approach of interest given its abscopal effect.
Researchers conducted multiomic analyses of 293 serial tissue and blood samples from 72 patients with metastatic NSCLC in a phase II clinical trial of stereotactic body radiation therapy followed by pembrolizumab vs immunotherapy alone. The samples were representative of the patients before treatment and after 3 to 6 weeks of treatment. They focused on the immunostimulatory effects of the radiation therapy at a cellular and molecular level.
Key Study Findings
Patients with immunologically “cold” tumors that express low tumor mutation burden, no PD-L1 expression, and/or Wnt pathway mutations were more likely to achieve a significantly longer progression-free survival with the addition of stereotactic body radiation therapy to pembrolizumab. These patients showed interferon-γ, interferon-α, and antigen processing as well as enriched presentation gene sets in nonirradiated tumor sites after receiving the stereotactic body radiation therapy.
Further, the researchers found that with treatment, these patients had expanding new and preexisting T-cell clones in the tumors and blood compartments, as well as clonal neoantigen-reactive autologous T-cell responses. “It was super exciting.... We not only captured the abscopal effect, but we linked the immune response with clinical outcomes in tumors where one would not expect to see immunotherapy responses,” said Dr. Anagnostou.
“Our findings highlight how radiation can bolster the systemic antitumor immune response in lung cancers unlikely to respond to immunotherapy alone,” stated lead study author Justin Huang, Undergraduate Research Assistant at Johns Hopkins University, who led the multiomic analyses. “Our work underscores the value of international, interdisciplinary collaboration in translating cancer biology insights to clinical relevance.”
Building on this research, the study authors are trying to track the immune system’s response to immunotherapy with liquid circulating tumor DNA testing. Findings from this study were presented at the 2025 American Association for Cancer Research Annual Meeting (Abstract 3772).
Disclosure: This study was supported by the National Institutes of Health and the Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy. For full disclosures of the study authors, visit nature.com.
