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.

免疫系统能够抑制恶性肿瘤。然而，免疫监视反应的类别及其肿瘤感知模式仍未被完全理解。在此，我们发现，尽管透明细胞肾细胞癌（ccRCC）被耗竭表型的CD8 + T细胞浸润，且这种浸润与患者预后呈负相关，但嫌色性肾细胞癌有大量表达颗粒酶A的上皮内1型天然淋巴细胞（ILC1s）浸润，这与患者生存呈正相关。白细胞介素 - 15（IL - 15）促进ILC1颗粒酶A的表达和细胞毒性，并且在嫌色性肾细胞癌肿瘤组织中IL - 15的表达与ILC1反应呈正相关。一个ILC1基因特征也可预测一部分乳腺癌患者的生存情况，且与IL - 15的表达相关。值得注意的是，ILC1s与癌细胞直接相互作用，并且在一个小鼠乳腺癌模型中，癌细胞产生的IL - 15支持ILC1s的扩增和抗肿瘤功能。因此，ILC1对癌细胞IL - 15的感知定义了一种上皮恶性肿瘤的免疫监视机制。