Researchers at Harvard Medical School (HMS) have created spatial maps of melanoma tumors at single-cell resolution, revealing a war of attrition in which cancerous cells suppress the lethal activity of immune cells over time. The information could lead to better ways of diagnosing and treating skin and other cancer types. The study, publihed in the 11 April 2022 issue of Cancer Discovery provides a dynamic view of the immune-suppressing capabilities of melanoma cells at an unprecedented resolution.
“We’re able to see everything from normal skin to early lesions to invasive melanoma, sometimes all in one piece of tissue,” said Sandro Santagata, M.D., Ph.D., Associate Professor of Pathology at Brigham and Women’s Hospital and co-senior author on the paper with Peter Sorger, Ph.D., Professor of Systems Pharmacology. “You end up with this map of how melanoma is developing right in front of you.”
The maps reveal what Santagata describes as “the battle between tumor cells and immune cells” that results in melanoma succumbing when immune cells are victorious, and melanoma progressing when tumor cells win.
Cancer has been long considered a disease of the genome, explained said lead author Ajit Nirmal, HMS research fellow. “Recent studies, however, have begun to show the importance of the tumor’s local microenvironment that nurtures and sustains these dangerous cells,” he said.
In the current study, the researchers combined high-resolution microscopy with single-cell transcriptomics (the sum of all RNA transcription by a cell) to study immune evasion and immunoediting in primary melanoma. Immune evasion is the process by which tumor cells are able to avoid recognition by immune system cells that would normally recognize them as foreign and destroy them. Immunoediting is the process that results in immune-resistant cancer cells.
Previous studies using single-cell technologies identified cell types and cell states making up the tumor microenvironment. What researchers have not known until now is the spatial relationships between these cell types and how they organize themselves in a way that provides a favorable environment for the tumor to develop. “Advancements in spatial omics allow us to build a Google Maps-like view of the skin to study what is exactly happening that allows the tumors to develop,” Nirmal said.
In melanoma, the first-line therapy is surgery if any abnormality is even suspected. Tumor boundaries are often unclear, making complete removal difficult. “A biological understanding of the development process will allow us to develop biomarkers for better diagnosis of early lesions and deliver adjuvant therapies after the primary treatment, to destroy any remaining cancer cells,” Nirmal said.
The current study would not have been possible even five years ago, Nirmal said. The early proof-of-concept studies for multiplexed imaging and multiplexed spatial RNA detection were published in early 2012-2014. Only in the last couple of years, significant improvements in experimental and computational methodologies have allowed researchers to apply these technologies to biological questions.
The HMS team is currently working with much larger sets of early melanomas to identify characteristics that allow the tumors to recur locally and metastasize. The team also hopes others will apply their techniques to other cancer types. “We have only scratched the surface of the data,” Nirmal said. “Further development of these technologies can have enormous potential for personalized medicine that goes beyond the conventional tumor-centric drug targeting but rather by considering cancer as a systemic disease where we target the tumor eco-system as a whole.”
