There is a growing appreciation for SASP as a prime example of the critical crosstalk between inflammation and cellular senescence, which is exploited in tumorigenesis, metastasis, immune evasion, and therapy resistance in SCC. miR-146a is a potent regulator of the inflammatory response through its modulation of IRAK1, NFkB and the proinflammatory chemokine, IL-8. The cadherin desmoglein 2 (Dsg2), which plays essential roles in cell proliferation and migration, is upregulated in many cancers and reduces both cellular and exosome-associated miR-146a, thus increasing IL-8. Here, Visium spatial transcriptomic and single cell RNAseq confirmed that Dsg2 and IL-8 are co-expressed at the leading edge of HNSCC tumors. RNAseq for miRNAs in CD9/63/81-positive exosomes from patient plasma showed miR-146a was lower in those who did not respond to treatment with the PD-1 inhibitor, nivolumab. To explore the consequences of miR-146a restoration in these cells in vitro, we utilized the XMIRXpress system, which facilitates the overexpression of miR-146a in cells and its loading into exosomes. Overall, In HPVpos UMSCC104 cells, miR-146a reduced IRAK1 and IL-8 and promoted cell death. However, in highly aggressive HPVneg UMSCC1 cells, miR-146a enhanced SASP including a decrease in metabolic activity with no change in cell viability and a shift to the G0/G1 phase with a reduction in nuclear size. Analysis of NFkB pathway genes by qPCR showed reduced IRAK1 and PD-L1 but a compensatory up-regulation of IL-8. And in conjunction with these attributes, an increase in cellular migration was observed. Taken together, these results suggest that the Dsg2/miR-146/IL-8 signaling axis plays a role in distinct tumor cell subsets in HNSCC through its modulation of SASP. And furthermore, that treatment with miR-146a may render these tumors more responsive to ICI therapy.

ESDR266 - The exosome-associated miR-146a modulates cellular senescence and senescence-associated secretory phenotype (SASP) in Head and Neck SCC (HNSCC)

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.