An Intraepithelial ILC1-like Natural Killer Cell Subset Produces IL-13

Sainiteesh Maddineni ¹ Krishna Sharma ¹ Imran A Mohammad ¹ Alistaire D Ruggiero-Sherman ¹ Ivan Stepanek ¹ June Ho Shin ¹ Jennifer K Bando ² John B Sunwoo ^1*

• ¹ Department of Otolaryngology, School of Medicine, Stanford University, Stanford, California, United States
• ² Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, California, United States

Natural killer (NK) cells are innate immune effectors with considerable heterogeneity and potent antitumor capabilities. Intraepithelial ILC1 (ieILC1)-like NK cells, a population of cytotoxic tissue-resident innate lymphoid cells, have recently been documented in the microenvironment of head and neck squamous cell carcinomas (HNSCC) and other solid tumors. These cells have antitumor cytolytic potential and are potent producers of type 1 cytokines, including IFN. Here, we identify a subpopulation of ex vivo differentiated ieILC1-like NK cells that produce IL-13 upon stimulation. Functional characterization revealed that these cells co-expressed IFN and IL-13 while maintaining an ILC1 transcriptional signature. IL-13 was induced either upon co-culture with tumor cell lines, or in response to TGF- and IL-15. IL-13-expressing ieILC1-like NK cells were identified among tumor infiltrating lymphocytes expanded from patient HNSCC tumors, in support of their existence in primary tumors. These data demonstrate additional heterogeneity within the ieILC1-like NK cell population than previously appreciated and highlight a unique form of ILC plasticity in which cells with clear ILC1 transcriptional profiles express a type 2 cytokine. With the known roles of IL-13 in cancer cell growth dynamics and immunoregulation, the identification of this subset within tumor microenvironments presents a potential target for therapeutic manipulation.