Lung Cancer Induces NK Cell Contractility and Cytotoxicity Through Transcription Factor Nuclear Localization

Darren Chen Pei Wong; E Hui Clarissa Lee; Junzhi Er; Ivan Yow; Ricky Abdi Gunawan Koean; Owen Ang; Jingwei Xiao; Boon Chuan Low; Jeak Ling Ding

doi:10.3389/fcell.2022.871326

Lung Cancer Induces NK Cell Contractility and Cytotoxicity Through Transcription Factor Nuclear Localization

Front Cell Dev Biol. 2022 May 16:10:871326. doi: 10.3389/fcell.2022.871326. eCollection 2022.

Authors

Darren Chen Pei Wong^{1

2}, E Hui Clarissa Lee¹, Junzhi Er¹, Ivan Yow², Ricky Abdi Gunawan Koean¹, Owen Ang¹, Jingwei Xiao², Boon Chuan Low^{1

2

3}, Jeak Ling Ding^{1

4}

Affiliations

¹ Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
² Mechanobiology Institute Singapore, National University of Singapore, Singapore, Singapore.
³ University Scholars Programme, National University of Singapore, Singapore, Singapore.
⁴ Integrative Sciences and Engineering Programme, National University of Singapore, Singapore, Singapore.

Abstract

Actomyosin-mediated cellular contractility is highly conserved for mechanotransduction and signalling. While this phenomenon has been observed in adherent cell models, whether/how contractile forces regulate the function of suspension cells like natural killer (NK) cells during cancer surveillance, is unknown. Here, we demonstrated in coculture settings that the evolutionarily conserved NK cell transcription factor, Eomes, undergoes nuclear shuttling during lung cancer cell surveillance. Biophysical and biochemical analyses revealed mechanistic enhancement of NK cell actomyosin-mediated contractility, which is associated with nuclear flattening, thus enabling nuclear entry of Eomes associated with enhanced NK cytotoxicity. We found that NK cells responded to the presumed immunosuppressive TGFβ in the NK-lung cancer coculture medium to sustain its intracellular contractility through myosin light chain phosphorylation, thereby promoting Eomes nuclear localization. Therefore, our results demonstrate that lung cancer cells provoke NK cell contractility as an early phase activation mechanism and that Eomes is a plausible mechano-responsive protein for increased NK cytotoxicity. There is scope for strategic application of actomyosin-mediated contractility modulating drugs ex vivo, to reinvigorate NK cells prior to adoptive cancer immunotherapy in vivo (177 words).

Keywords: Eomesdermin (Eomes); NK-cancer cell interaction; TGFβ disparate role; actin cytoskeleton; cellular contractility of natural killer (NK) cell; mechanotransduction in NK cells; non-small cell lung cancer (NSCLC, invasive and non-invasive subtypes); transcription factor shuttling.