Cutaneous Squamous Cell Carcinoma Development Is Associated with a Temporal Infiltration of ILC1 and NK Cells with Immune Dysfunctions

Innate Lymphoid Cells: New Targets for Cutaneous Squamous Cell Carcinoma Immunotherapy

“…ILCs abundance in the skin and mucosal tissues; their high infiltration in cancers of the barrier organs, including esophagus, stomach, lung, and colon; and their ability to secrete IFN-g and TNF-a raise the possibility that they can play an antitumor role in cSCC development. In addition, on the basis of Luci et al (2021) and other publications, the enrichment of ILC2s in healthy skin versus the high infiltration of ILC1s in the precancerous papilloma stage indicates a potential plasticity in ILC regulation in the skin that may evolve from one subtype to another in response to TME signals. Importantly, ILC2s can convert to ILC1s when exposed to IL-1b and IL-12 by upregulating the T-bet transcription factor (Bal et al, 2016;Ohne et al, 2016).…”

“…In contrast, the upregulation of inhibitory receptors such as TIGIT, PD-1, LAG3, and CTLA4 on ILCs in the TME has been found to be associated with tumor progression (Crinier et al, 2020). Luci et al (2021) showed an upregulation of inhibitory receptors CTLA4 and PD-1 on ILC1 and NK cells at the papilloma and tumor stages of cSCC development, and the authors highlighted the TIGIT-induced inhibitory axis on NK cells to be prominent in human cSCC (Figure 1). This finding is supported by the TIGITmediated NK cell exhaustion in cancer and the inhibition of tumor growth by blocking TIGIT, which can be a promising strategy for cSCC immunotherapy (Zhang et al, 2018).…”

“…Harnessing ILCs for cSCC immunotherapy NK cells and ILC1s show altered functional repertoires in cancer. Luci et. al.…”

“…NK cell function in cSCC Luci et al (2021) investigated the function of NK cells and ILC1s in mouse and human cSCC. Using skin chemical carcinogenesis and murine cSCC cell line graft models, they showed a requirement for NK cells at a precancerous stage for protection against early cSCC development.…”

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The importance of innate immune cells in cancer promotion has been long recognized. Luci et al (2021) show a key role for innate lymphoid cells (ILCs) in controlling precancerous skin lesions and impaired function of NK cells and ILC1s during progression to cutaneous squamous cell carcinoma (cSCC). These results, together with other findings, suggest that activation of ILCs could serve as a novel immunotherapeutic strategy against cSCC.

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