CD39+CD49a+CD103+ cytotoxic tissue-resident natural killer cells infiltrate and control solid epithelial tumor growth in mice

Human tissue-resident natural killer (NK) cells (trNK cells), broadly defined by markers of tissue residency, such as CD49a [integrin α₁ (ITGA1)] and CD103 [integrin α_E (ITGAE)], are increasingly recognized for their immunoregulatory role in host control of infection, malignancy, and autoimmunity. Although the importance of transforming growth factor–β in trNK cell differentiation has been demonstrated, the context in which the differentiation of CD49a⁺CD103⁺ trNK cells occurs can result in either an immunosuppressive phenotype (e.g., decidual NK cells) or a highly cytotoxic one (e.g., some tumor trNK subsets). To understand this dichotomy better, we used a multiomic approach to molecularly characterize these cells. We identified a cytotoxic trNK (ctrNK) cell population, characterized by the expression of CD39. These ctrNK cells exhibited superior cytolytic activity against tumor target cells, enhanced capacity to infiltrate into solid tumor microenvironments, and augmented ability to control solid tumor growth in vivo compared with conventionally activated peripheral NK cells. This heightened cytolytic and infiltrative functionality of ctrNK cells appeared to be conferred, in part, by the expression of CD103 and by avidity for tumor targets. Because adoptive immune cell therapy of solid tumor malignancies has been challenged by the inefficiency of ex vivo expanded immune cells to infiltrate immunosuppressive solid tumor microenvironments, our observations that ctrNK cells can be differentiated and expanded ex vivo present a potential platform for adoptive cell therapy of solid tumor malignancies.