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Updated: Jan 2, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Discovery of specialized NK cell populations infiltrating human melanoma metastases
Lucas Ferrari de Andrade1,2,3, Yuheng Lu4, Adrienne Luoma1,2
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Abstract:
NK cells contribute to protective antitumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we performed single-cell RNA-seq analysis of NK cells isolated from human melanoma metastases, including lesions from patients who had progressed following checkpoint blockade. This analysis identified major differences in the transcriptional programs of tumor-infiltrating compared with circulating NK cells. Tumor-infiltrating NK cells represented 7 clusters with distinct gene expression programs indicative of significant functional specialization, including cytotoxicity and chemokine synthesis programs. In particular, NK cells from 3 clusters expressed high levels of XCL1 and XCL2, which encode 2 chemokines known to recruit XCR1+ cross-presenting DCs into tumors. In contrast, NK cells from 2 other clusters showed a higher level of expression of cytotoxicity genes. These data reveal key features of NK cells in human tumors and identify NK cell populations with specialized gene expression programs.
Insights
This study reveals distinct functional states of Natural Killer (NK) cells within human melanoma tumors. These tumor-infiltrating NK cells exhibit specialized gene expression programs, impacting antitumor immunity.
Area of Science:
- Immunology
- Cancer Biology
- Single-cell Genomics
Background:
- Natural Killer (NK) cells are crucial for antitumor immunity.
- The functional states of NK cells within human solid tumors remain largely uncharacterized.
Purpose of the Study:
- To investigate the transcriptional programs and functional specialization of NK cells infiltrating human melanoma metastases.
- To identify distinct NK cell populations in tumors, particularly in patients progressing after checkpoint blockade therapy.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was employed to analyze NK cells from human melanoma lesions.
- Comparative analysis was performed between tumor-infiltrating NK cells and circulating NK cells.
Main Results:
- Significant transcriptional differences were observed between tumor-infiltrating and circulating NK cells.
- Seven distinct clusters of tumor-infiltrating NK cells were identified, each with specialized gene expression programs.
- Specific NK cell clusters showed high expression of chemokines (XCL1, XCL2) for dendritic cell recruitment, while others prioritized cytotoxicity gene expression.
Conclusions:
- NK cells in human melanoma exhibit significant functional specialization within the tumor microenvironment.
- These findings highlight specific NK cell subsets with potential roles in recruiting immune cells and mediating tumor cell killing.
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