Increased tissue-resident memory T (TRM) cells and STAT3 expression in cutaneous lupus erythematosus patients refractory to antimalarials

Summary: Antimalarials are the first-line therapy for cutaneous lupus erythematosus (CLE). While some of the patients that do not initially respond to hydroxychloroquine (HCQ) benefit from the addition of quinacrine (QC), there is a subset of patients that are refractory to both antimalarials. We investigated the immunologic characteristics of patients that respond to antimalarials versus nonresponders. CLE patients were classified as HCQ-responders, HCQ/QC-responders, or HCQ/QC-nonresponders. Immunohistochemistry and qRT-PCR for gene expression were used to characterize the inflammatory cell composition and cytokine expression in lesional skin biopsies from patients. Immunohistochemistry showed that tissue-resident memory T (TRM) cells were significantly higher in HCQ/QC-nonresponders compared to HCQ- and HCQ/QC-responders (p<0.05). While myeloid DCs were significantly higher in HCQ/QC-responders compared to HCQ- and HCQ/QC-nonresponders, plasmacytoid DCs, neutrophils, macrophages, and autoreactive T cells did not differ significantly among the three groups. The HCQ/QC-nonresponder group was distinct from the other groups in that their CLASI scores did correlate positively with the number of TRM cells (r=0.6335, p<0.05) and macrophages (r=0.5726, p<0.05). Analyzing the mRNA expression demonstrated a high STAT3 expression in HCQ/QC-nonresponders. Staining also showed IL-22 expression was significantly higher in HCQ/QC-nonresponders versus the HCQ- or HCQ/QC-responders while IL-17 expression was not significantly different between groups. In conclusion, an increased number of TRM cells and correlation between TRM cells and macrophages with CLASI scores in the HCQ/QC-nonresponders, a finding not seen in either HCQ or HCQ/QC-responders, may indicate that TRM cells and macrophages are more involved in antimalarial-refractory skin disease.