Unraveling the phenotypic features and functional mechanisms of tumor-associated adaptive natural killer cells

<p dir="ltr">Adaptive natural killer (aNK) cells represent a specialized subset of NK cells that can form immunological memory, once thought to belong exclusively to, a group of adaptive immune cells, T and B cells. This discovery has fundamentally challenged the traditional dichotomy between innate and adaptive immunity, highlighting that NK cells are capable not only of rapid innate responses but also of long-term functional adaptation. While their role in viral infection is increasingly understood, including their contribution to long-lasting protection and recall responses, their presence, regulation, and antigen specificity in solid tumors remain less explored and thus represent an important knowledge gap in tumor immunology. <br><br>In this thesis, we investigated aNK cells in the context of high-grade serous ovarian cancer (HGSOC). In study I, we found that tumor-infiltrating aNK cells are associated with enhanced autologous tumor killing, suggesting a direct role in tumor surveillance, and that naïve NK cells could be trained in vitro to possess immune memory-like behavior through exposure to tumor antigens, demonstrating that tumor-derived signals are sufficient to imprint memory-like features (Paper I). In study II, we used integrated single-cell transcriptomic and chromatin accessibility analysis to uncover key transcriptional regulators-PRDM1 and STAT2-and downstream target genes, CRCP and MTFP1, that define the epigenetic landscape of tumor-infiltrating aNK cells, providing mechanistic clue into how these cells acquire and maintain their unique identity in the tumor microenvironment (Paper II). In study III, we showed that aNK cells recognize non-canonical 9mer viral peptides presented by HLA-E (Paper III), and further discovered a novel tumor-derived peptide that also binds HLA-E and effectively trains aNK cells to generate enhanced memory responses against ovarian tumor cells, thereby establishing a direct link between tumor antigens and the induction of NK cell memory (Paper IV). <br><br>Together, these findings deepen our understanding of peptide-driven memory in NK cells and reveal new opportunities for harnessing aNK cells in cancer immunotherapy, either through targeted manipulation of their regulatory networks or by exploiting tumor-associated peptides to potentiate durable antitumor response.<br><br><b>List of scientific papers</b><br><br>I. <b>Sun Y</b>, Rodgers-Furones A, Gultekin O; Khare S, Neo SY, Shi W, Galceran LM, Lam K-P, Dasgupta R, Fuxe J, Salehi S, Lehti K, Sarhan D. Adaptive NK Cells Exhibit Tumor-Specific Immune Memory and Cytotoxicity in Ovarian Cancer. Cancer Immunol Res, 2025 Jul 2;13(7):1080-1097. PMID: 40293356. <a href="https://doi.org/10.1158/2326-6066.cir-24-0852" rel="noreferrer" target="_blank">https://doi.org/10.1158/2326-6066.cir-24-0852</a><br><br>II. <b>Sun Y</b>, Wan M, Kolbeinsdottir S, Wang K, Khare S, Gultekin O, Salehi S, Lehti K, Dasgupta R, Foukakis T, Enge M, Sarhan D. Single-Cell Integration of Chromatin Accessibility and Transcriptomics Reveals Regulatory Networks in Ovarian Tumor-Infiltrating Adaptive NK Cells. bioRxiv. 2025 Sep 13. [Manuscript Preprint] doi: <a href="https://doi.org/10.1101/2025.09.13.676040" rel="noreferrer" target="_blank">https://doi.org/10.1101/2025.09.13.676040</a><br><br></p><p dir="ltr">III. Martín Almazán N, Sala BM, Sandalova T, <b>Sun Y</b>, Resink T, Cichocki F, Söderberg-Nauclér C, Miller JS, Achour A, Sarhan D. Non-classical HLA-E restricted CMV 15-mer peptides are recognized by adaptive NK cells and induce memory responses. Front Immunol. 2023 Sep 21;14:1230718. PMID: 37809084; PMCID: PMC10552778. <a href="https://doi.org/10.3389/fimmu.2023.1230718" rel="noreferrer" target="_blank">https://doi.org/10.3389/fimmu.2023.1230718</a> <br><br>IV. <b>Sun Y</b>, Kaminskiy Y, Branca R, Li S, Gultekin O, Govindajaran K, Salehi S, Lehtio J, Sarhan D. Recognition of Ovarian Tumor-Derived Non-canonical Peptide Induces Memory-Like Features in Natural Killer Cells. bioRxiv. 2025 Sep 15. [Manuscript Preprint] doi: <a href="https://doi.org/10.1101/2025.09.15.676162" rel="noreferrer" target="_blank">https://doi.org/10.1101/2025.09.15.676162</a></p>