Cytotoxic Innate Lymphoid Cells Sense Cancer Cell-Expressed Interleukin-15 to Suppress Human and Murine Malignancies

Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that while clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8+ T cells which negatively correlated with patient prognosis, chromophobe RCC had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies. We conducted single cell RNA-sequencing of a single patient with advanced stage kidney cancer and chromophobe subtype. We analyzed CD45+ cells with a focus on innate lymphoid cells, conventional NK cells, and CD8+ Exhausted cells. These data were used to develop a gene signature of ILCs and CD8 Exhausted cells, and to inform validation experiments in larger cohorts of RCC patients.