Merkel cell carcinoma is a rare but highly aggressive form of skin cancer 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 half of patients do not respond to this therapy. A new study published today in Discovery of Cancer provides insight into why some patients with Merkel cell carcinoma respond to this type of immunotherapy while others do not.
In collaboration with scientists at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center, Moffitt Cancer Center researchers conducted the largest and most comprehensive study to date of Merkel cell carcinoma. They analyzed samples from 116 patients using advanced multimodal techniques -? tumor and monocyte RNA sequencing, spatial transcription and multiplexed immunofluorescence -? gain insights into the immune response and tumor characteristics. Their findings reveal that specific cells of the immune system, particularly tissue-resident CD8 T cells and γδ T cells, play a critical role in the body’s response to immune checkpoint blockade therapy.
The research team, led by Kenneth Tsai, MD, Ph.D., vice president of Pathology Research at Moffitt, and Jaehyuk Choi, MD, Ph.D., at Northwestern University, discovered that those who respond to immune checkpoint blockade treatment have higher levels of pre-existing tissue CD8 T cells or Vδ1 γδ T cells within their tumors. These cells exhibit unique transcriptional programs and clonal expansion that reflect antigen specificity, meaning they can effectively recognize and attack cancer cells. In contrast, tumors from those not responding to immunotherapy showed increased proliferation and markers associated with neural stem cells, as well as the inflammatory molecule IL-1.
Using spatial transcription, the researchers demonstrated that these beneficial T cells are often in close proximity to other immune cells such as B cells and dendritic cells, which help boost their activity by providing the necessary chemokines and costimulation. This close cellular interaction within the tumor microenvironment is a key factor in the efficacy of the immune response.
“Our findings not only highlight the possibility of using specific genes and immune cells as biomarkers to predict patient response to immune checkpoint blockade therapy, but also suggest several approaches to abolish resistance and enhance efficacy,” Chai said. “Importantly, patients with tumors that already contained the right mix of immune cells before treatment were more likely to respond, suggesting that increasing their numbers in the right location could enhance treatment results.”
The department of cutaneous oncology and the Donald A. Adam Melanoma and Skin Cancer Center of Excellence at Moffitt provided critical support and represent leading clinical and research expertise in Merkel cell carcinoma.
This research was supported by the National Institutes of Health (DP2 OD024475-0, R35 GM144083P30 CA076292, P30 AR075049, P30 CA060553, T32 CA009560 and F30CA278201, Research Foundation, Barukemia and Lymphoma Society (1377- 21).
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Journal Reference:
Reinstein, ZZ, et al. (2024) Preexisting Skin-Resident CD8 and γδ T Cell Circuits Mediate the Immune Response to Merkel Cell Carcinoma and Predict Immunotherapy Efficacy. Discovery of Cancer. doi.org/10.1158/2159-8290.CD-23-0798.
