Uniquely NK cells : the multifaceted roles of the natural killers

Natural killer cells (NK cells) were primarily discovered through the study of tumor cell recognition during immune surveillance. Till date, many studies had characterized NK cells to have immune regulatory roles in both physiological and pathological context. In cancer, the prevalence of cytotoxic NK cells in the tumor does not always predict for better clinical prognosis. In the present thesis, the multi-faceted roles of tumor-educated NK cells were studied in parallel with clinical investigations in which we highlighted the significance of the different cell-cell interactions between NK cells and the microenvironment in the progression of cancer.

In Paper 1, we identified a distinct immune-suppressive subset of NK cells expressing CD73 within breast cancer and sarcoma tumors and observed that high frequencies of CD73+ NK cells correlated with larger breast tumors in our clinical cohort. The emphasis of paper 1 demonstrated how tumor cells could hijack NK cells as a means of immune evasion. Not only did these NK cells acquired the expression of CD73 and multiple immune exhaustion markers, but they also upregulated the production of other suppressive cytokines such as IL-10 and TGFb which acts to inhibit T cell activation and proliferation.

As we further explored into factors regulating NK cell immune activation, Paper 2 identified that NK cells were highly susceptible to immune suppression mediated by reactive oxygen species (ROS). Tumor-infiltrating NK cells possess high surface thiol densities as means to persist in the tumor microenvironment with high oxidative stress. It was also demonstrated that NK cells with high surface thiol density could be considered as “helper” NK cells as ROS could be neutralized by these NK cells to protect T cells in proximity.

Paper 3 continued to highlight the importance of physical cell-cell interactions was not only between tumor and NK cells but also the interplay between NK cells and myeloid cells residing in the microenvironment. In several clinical cohorts, a co-abundance of NK cell and myeloidderived suppressor cells (MDSC) gene signatures were observed in non-responders to immune checkpoint therapy. Through patient-derived in vitro and in vivo models, we demonstrated that the presence of NK cells hinders myeloid-dependent antigen presentation and potentiate the suppressive capacity of STAT3-activated MDSCs via the production of IL-6.

Taken together, the present thesis proposed several non-canonical functions of NK cells in cancer biology that could potentially have a significant impact on the response of patients towards cancer immunotherapies. The balance of “good” and “bad” NK cells is heavily influenced by both soluble factors and the variety of cellular interactions within the microenvironment. While the general scientific community has a stronger interest to harness NK cells for therapeutic applications, the collective data presented in this phD thesis highlighted the complexity of NK cell biology with the hope to motivate future investigations to uncover deeper understandings of NK cells within the tumor immune landscape.

List of scientific papers

I. Neo SY, Yang Y, Record J, Ma R, Chen X, Chen Z, Tobin NP, Blake E, Seitz C, Thomas R, Wagner AK, Andersson J, de Boniface J, Bergh J, Murray S, Alici E, Childs R, Johansson M, Westerberg LS, Haglund F, Hartman J, Lundqvist A. CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment. J Clin Invest. 2020;130(3):1185-98.
https://doi.org/10.1172/JCI128895

II. Yang Y*, Neo SY*, Chen Z, Cui W, Chen Y, Guo M, Wang Y, Xu H, Kurzay A, Alici E, Holmgren L, Haglund F, Wang K, Lundqvist A. Thioredoxin activity confers resistance against oxidative stress in tumorinfiltrating NK cells. J Clin Invest. 2020;130(10):5508-22. *Both authors contributed equally.
https://doi.org/10.1172/JCI137585

III. Shi Yong Neo, Le Tong, Yaxuan Liu, Mariana Oliveria, Yi Chen, Chen Ziqing, Chen Xinsong, Ma Ran, Lim Jia Pei, Alici Evren, Wickström Stina L, Haglund Felix, Hartman Johan, Kiessling Rolf, Lisa Westerberg, Andreas Lundqvist. Tumor-associated NK cells drive the development of MDSCs via IL-6/STAT-3 Axis. [Manuscript]