Decidual-Like Natural Killer Cells Are Enriched in Melanomas and Acquire CD9 Through Melanoma Cell Contact

Natural killer (NK) cells at the maternal-fetal interface harbor a specialized decidual phenotype that promotes placentation and immune tolerance. Although it has been postulated that tumors can exploit similar NK cell programs to augment the tumor microenvironment, this mechanism has not been investigated in melanoma. Using flow cytometry and multiplex immunohistochemistry, we identified CD56 ^Bright CD16 ^- CD49a ⁺ CD9 ⁺ decidual-like NK (dl-NK) cells within melanoma tumors; these cells were rare or absent in peripheral blood from either patients with melanoma or healthy donors. These dl-NK cells were detected within and surrounding melanoma tumors in both male and female patients and across melanoma subtypes and across primary, lymph node, and distant metastatic sites. In an exploratory cohort of patients treated with tumor-infiltrating lymphocyte therapy, higher dl-NK frequency was observed in the patient with progressive disease. Because CD9 is a defining feature of decidual NK cells, we examined the relationship of CD9 with the dl-NK phenotype. Tumor CD9 expression was positively associated with intratumoral dl-NK frequency (Pearson rho = 0.40, p = 0.056). Direct co-culture of healthy donor NK cells with CD9-expressing melanoma cells induced robust CD9 acquisition by CD56 ^Bright NK cells, whereas separation by a transwell abrogated this effect, demonstrating a requirement for direct cell-cell interaction. Collectively, these findings identify a dl-NK cell population within melanomas and suggest that direct interactions with melanoma cells may contribute to acquisition of this phenotype, revealing a potential immunologic parallel between the melanoma microenvironment and the maternal-fetal interface.