Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans

Ludin, A.; Stirtz, G. L.; Tal, A.; Nirmal, A. J.; Besson, N.; Jones, S. M.; Pfaff, K. L.; Manos, M.; Liu, S.; Barrera, I.; Gong, Q.; Rodrigues, C. P.; Sahu, A.; Jerison, E.; Alessi, J. V.; Ricciuti, B.; Richardson, D. S.; Weiss, J. D.; Moreau, H. M.; Stanhope, M. E.; Afeyan, A. B.; Sefton, J.; McCall, W. D.; Formato, E.; Yang, S.; Zhou, Y.; Hoytema van Konijnenburg, D. P.; Cole, H. L.; Cordova, M.; Deng, L.; Rajadhyaksha, M.; Quake, S. R.; Awad, M. M.; Chen, F.; Sorger, P. K.; Hodi, F. S.; Rodig, S. J.; Murphy, G. F.; Zon, L. I.

doi:10.1101/2024.09.18.613595

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bioRxiv · 10.1101/2024.09.18.613595

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans

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Abstract

Immunotherapy leads to cancer eradication despite the tumors immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules. The craters harbor the highest density of CD8+ T cells in the tumor. In zebrafish, CD8+ T cells formed prolonged interactions with melanoma cells within craters, characteristic of antigen recognition. Following immunostimulatory treatment, the craters enlarged and became the major site of activated CD8+ T cell accumulation and tumor killing that was B2M dependent. In humans, craters predicted immune response to ICB therapy, showing response better than high T cell infiltration. This marks craters as potential new diagnostic tool for immunotherapy success and targets to enhance ICB response.

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Ludin, A., Stirtz, G. L., Tal, A., Nirmal, A. J., Besson, N., Jones, S. M., Pfaff, K. L., Manos, M., Liu, S., Barrera, I., Gong, Q., Rodrigues, C. P., Sahu, A., Jerison, E., Alessi, J. V., Ricciuti, B., Richardson, D. S., Weiss, J. D., Moreau, H. M., Stanhope, M. E., Afeyan, A. B., Sefton, J., McCall, W. D., Formato, E., Yang, S., Zhou, Y., Hoytema van Konijnenburg, D. P., Cole, H. L., Cordova, M., Deng, L., Rajadhyaksha, M., Quake, S. R., Awad, M. M., Chen, F., Sorger, P. K., Hodi, F. S., Rodig, S. J., Murphy, G. F., Zon, L. I.. 2024-09-19. Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans. https://doi.org/10.1101/2024.09.18.613595

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