Adaptations of human lung NK cells to an intratumoral environment — ASN Events
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  2. Poster Session One
  3. Adaptations of human lung NK cells to an intratumoral environment

Adaptations of human lung NK cells to an intratumoral environment (#110)

Demi Brownlie 1 , Elena Bonaiti 1 , Nicole Wild 1 , Jesper Säfholm 2 3 , Jeff Mold 4 , Kasra Vali Jalali 5 , Igor Schliemann 6 7 , Ozan Aricak 6 8 , Felix Haglund de Flon 6 7 , Carl-Johan Eriksson 4 , Hans-Gustaf Ljunggren 9 , Evren Alici 1 , Jakob Michaëlsson 9 , Nicole Marquardt 1
  1. Center for Hematology and Regenerative Medicine, Dept. of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden
  2. Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  3. Dept. of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
  4. Dept. of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
  5. Thoracic Surgery, Heart and Vascular Center, Karolinska University Hospital , Stockholm, Sweden
  6. Dept. of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Sweden
  7. Dept. of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
  8. Dept. of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Huddinge, Sweden
  9. Center for Infectious Medicine, Dept. of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden

Background: Natural killer (NK) cells are key players in targeting malignant cells, but their efficient use in immunotherapeutic strategies against lung cancers is complicated by the hypoxic and immunosuppressive tumor microenvironment (TME). The TME can affect NK cell phenotype and function, however, little is known about the adaptations of the NK cells within lung tumors.

Aims: In this study, we aimed at investigating the plasticity of NK cell subsets in the TME of human lung cancers and the role of hypoxia as an immune-modulating factor in the TME.

Methods: NK cell subsets were isolated from different sites (peritumoral tissue, tumor margin and center) of human lung tumors and characterized at protein and transcriptome levels by flow cytometry and scRNA-seq. Moreover, patient-matched lung and blood cells were cultured in vitro in hypoxia (2% O2) and normoxia (20% O2), and the NK cell phenotype was determined using high-parameter flow cytometry.

Results: We identified a novel intratumoral CD16+ NK cell subset co-expressing CD49a and/or CD103. This CD16+CD49a+ NK cell subset shared a similar phenotype with CD16- tissue-resident NK cells but displayed a more cytotoxic profile, despite the absence of perforin. Furthermore, scRNA-seq data suggested that NK cells, especially the CD16+CD49a+ subset, were influenced by the TME, with pathways related to immune checkpoints, immunosuppression, cellular stress response, and hypoxia/metabolism being upregulated in the tumor center. In vitro cell culture showed that lung NK cells were more susceptible to hypoxia than blood NK cells, resulting in a significant loss of perforin.

Conclusion: These findings indicate that the TME shapes the NK cell subsets at both phenotypical and functional level, and highlight the critical role of hypoxia in NK cell plasticity in human lung cancer. Thus, modulating hypoxia-induced adaptations of NK cells could enhance their efficacy in future therapeutical approaches against lung tumors.