Researchers may have uncovered why some patients with Merkel cell carcinoma do not respond to immune checkpoint blockade therapy, according to a recent study published by Reinstein et al in Cancer Discovery.
Background
Merkel cell carcinoma—a rare but highly aggressive type of skin cancer—is known for its rapid growth and tendency to metastasize. Despite the promise of immune checkpoint blockade therapy, which can boost the body’s immune response against cancer cells, nearly 50% of patients do not respond to this treatment.
Study Methods and Results
In the recent study, the researchers analyzed samples from 116 patients with Merkel cell carcinoma using advanced multimodal techniques—including bulk and single-cell RNA sequencing, spatial transcriptomics, and multiplexed immunofluorescence—to gain insights into the patients’ immune responses and tumor characteristics.
The researchers discovered that specific immune cells, particularly tissue-resident CD8 T cells and gamma-delta T cells, may play a crucial role in the body’s response to immune checkpoint blockade therapy.
The patients who responded to therapy had higher levels of preexisting tissue-resident CD8 T cells or V-delta 1 gamma-delta T cells within their tumors. These cells exhibited unique transcriptional programs and clonal expansion reflective of antigen specificity, demonstrating their ability to effectively recognize and attack cancer cells. In contrast, the tumors of patients who did not respond to immunotherapy showed increased proliferation and markers associated with neuronal stem cells as well as the inflammatory molecule interleukin-1.
Using spatial transcriptomics, the researchers revealed that these beneficial T cells are often found in close proximity to other immune cells like B cells and dendritic cells, which help enhance their activity by supplying necessary chemokines and costimulation. This close cellular interaction within the tumor microenvironment was a key factor in the effectiveness of the immune response.
Conclusions
“Our findings not only highlight the potential to use specific genes and immune cells as biomarkers for predicting patient response to immune checkpoint blockade therapy, but also suggest several approaches for abrogating resistance and enhancing efficacy,” underscored co–senior study author Kenneth Tsai, MD, PhD, Vice Chair of Pathology Research at Moffitt Cancer Center. “Importantly, patients with tumors already containing the right mix of immune cells before treatment were more likely to respond, suggesting that increasing their numbers with the correct localization could enhance treatment outcomes,” he concluded.
Disclosure: The research in this study was supported by the National Institutes of Health, the Barry S. Greene Fund, the V Foundation for Cancer Research, and the Leukemia and Lymphoma Society. For full disclosures of the study authors, visit aacrjournals.org.
