Accumulation of tissue-resident natural killer cells, innate lymphoid cells, and CD8⁺ T cells towards the center of human lung tumors

ABSTRACT

Lung cancer is a leading cause of cancer-related death worldwide. Despite recent advances in tissue immunology, little is known about the spatial distribution of tissue-resident lymphocyte subsets in lung tumors. Using high-parameter flow cytometry, we identified an accumulation of tissue-resident lymphocytes including tissue-resident NK (trNK) cells and CD8⁺ tissue-resident memory T (T_RM) cells toward the center of human non-small cell lung carcinomas (NSCLC). Chemokine receptor expression patterns indicated different modes of tumor-infiltration and/or residency between trNK cells and CD8⁺ T_RM cells. In contrast to CD8⁺ T_RM cells, trNK cells and ILCs generally expressed low levels of immune checkpoint receptors independent of location in the tumor. Additionally, granzyme expression in trNK cells and CD8⁺ T_RM cells was highest in the tumor center, and intratumoral CD49a⁺CD16⁻ NK cells were functional and responded stronger to target cell stimulation than their CD49a⁻ counterparts, indicating functional relevance of trNK cells in lung tumors.

In summary, the present spatial mapping of lymphocyte subsets in human NSCLC provides novel insights into the composition and functionality of tissue-resident immune cells, suggesting a role for trNK cells and CD8⁺ T_RM cells in lung tumors and their potential relevance for future therapeutic approaches.

KEYWORDS:

• CD8+ T cells
• ILC
• lung cancer
• NK cells
• tissue-resident
• tumor-infiltrating

Acknowledgements

We thank the volunteers who participated in the study and S. Hylander as well as the Thoracic Surgery Unit at Karolinska University Hospital for administrative and clinical help. We would also like to acknowledge P. Clavero for his assistance in the laboratory.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval and consent to participate

The Regional Ethical Review Board in Stockholm approved the study. All donors gave informed written consent prior to sample collection.

Data availability statement

The data that support the findings of this study are available from the corresponding author, NM, upon reasonable request.

Consent for publication

All authors are informed and consent to the publication of this data.

Authors- contributions

Conceptualization/study design: D.B., J.M., N.M.; Investigation: D.B., A.v.K., G.V., N.W., E.Y., J.M., N.M.; Resources: J.M., N.M., J.S., E.A., H.G.L., I.S., O.A., F.HdF.; Writing – original draft: D.B., G.V., N.W., J.M., N.M.; Writing – review and editing: D.B., N.W., E.A., O.A., H.G.L., J.M., N.M.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2233402

Additional information

Funding

This work was supported by the Swedish Research Council (NM: #2021-03069, HGL: #2020-01365), the Center for Innovative Medicine (CIMED, NM: #20200680, HGL: #2020-2022, JM: #20200725), the Swedish Cancer Society (NM: # 22 2319 Pj; HGL: #20 0975; JM: #20 1138, CAN 2017/663; FHdF: #19-0029), the Heart-Lung Foundation (JS: #20200659), the Magnus Bergvalls Foundation (NM: #2019-03168; JS: #2022), the Tornspiran Foundation (NM), the Åke Wibergs Foundation (JS), the Konsul Berghs Foundation (JS), Karolinska Institutet (NM), and Vinnova (HGL: #2020-2024).