Cancer immunotherapies can yield powerful, lasting effects and tumor regression. However, identifying patients and tumors in which these therapies can be most effective remains challenging. In this study, the authors used Cell DIVE to explore the phenotypes of tumor cells in patients who had received IL2 immunotherapy for the treatment of melanoma.
To develop a comprehensive overview of the cellular phenotypes and gene expression changes that underlie response to IL2 therapy, the authors identified seven patients suffering from multiple contemporaneous in-transit melanoma metastases and collected FFPE tissue blocks from these lesions. Importantly, in these patients, at least one lesion had been resected without IL2 therapy and at least one lesion had been resected following the therapy. In each of the collected lesions, the authors analyzed 28 proteins, 770 immune response genes, and genetic alterations in 468 cancer genes using genomics technologies and multiplex immunofluorescence enabled by Cell DIVE.
In about half of the IL2 injected lesions, tumor cells were no longer detectable after treatment. Instead, these lesions showed increased fractions of CD8+ T cells (particularly those in a non-exhausted state) as well as CD4+ helper and regulatory T cells, B cells, and natural killer (NK) cells.
The authors then turned their attention to biomarkers that might predict response to IL2 by comparing untreated lesions from patients who responded well to IL2 treatment with untreated lesions from patients who did not. A key difference between these two groups of lesions was the expression of MHC I on the surface of the tumor cells. Untreated lesions from responding patients featured MHC I+ in at least 75% of tumor cells whereas tumor cells from patients displayed a reduction in the proportion of cells featuring MHC I. Further analysis of the tumor microenvironment of untreated lesions in complete responders revealed many other signs of an immune environment primed to react to the presence of tumors, including interferon expression, IL2 response gene upregulation, and an increase in the number of exhausted CD8+ T cells. How these T cells in untreated lesions complete the switch from an exhausted to a non-exhausted state is a question for future research.
This complex study reveals the depth of information that multiplex imaging through Cell DIVE and subsequent phenotypic analysis can provide and illuminates for the first time many biomarkers of response to IL2 therapy in melanoma.
M. Pourmaleki. C. J. Jones, C. E. Ariyan, Z. Zeng, M. Pirun, D. A. Navarrete, Y. Li, M. Zhang, S. Nandakumar, C. Campos, S. Nadeem, D. S. Klimstra, C. F. Temple-Oberle, T. Brenn, E. J. Lipson, K. M. Schenk, J. E. Stein, J. M. Taube, M.G. White, R. Traweek, J. A. Wargo, J. M. Kirkwood, B. Gasmi, S. L. Goff, A. D. Corwin, E. McDonough, F. Ginty, M. K. Callahan, A. Schietinger, N. D. Socci, I. K. Mellinghoff, T. J. Hollmann:
Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma
Cancer Immunol Res (2022) 10 (3): 303–313.