Through their cytotoxic capacities and cytokine production, natural killer (NK) cells modulate autoimmune diseases. However, their role in the pathogenesis of systemic lupus erythematosus (SLE) has not been extensively studied. The aim of this study was to analyse the immunophenotypic and functional characteristics of the two major NK cell subsets in SLE and relate them with disease activity. Peripheral blood samples from 44 patients with active (n = 18) and inactive SLE (n = 26) and 30 controls were analysed by flow cytometry to evaluate NK cell subsets, according to: the differential expression of CXCR3 and CD57; expression of granzyme B and perforin; and production of interferon gamma (IFN-γ) and tumor necrosis alpha (TNF-α), after PMA/ionomycin activation. A clear decrease in absolute and relative numbers of circulating NK cells was found in SLE, particularly in active disease, while the proportions of the major NK cell subsets were unaffected. Active SLE was associated with a reduced CXCR3 expression on both NK cell subsets and a lower frequency of CD56(dim) NK cells expressing CXCR3. Furthermore, granzyme B expression was decreased in both SLE groups, but the percentage of NK cells expressing granzyme B and perforin was higher, particularly in active disease. We found a significant decrease in the percentage of CD56(bright) and CD56(dim) NK cells producing TNF-α and of its expression on CD56(dim) NK cells in active disease, while IFN-γ expression on CD56(bright) NK cells was increased in both SLE groups. Our findings suggest that NK cell subsets exhibit unique phenotypic and functional changes that are particularly evident in active SLE, and they may have the potential to affect the disease outcome.
1010 Background: The question of which is the best endocrine partner to CDK4/6 inhibitors in first line for ER+ HER2- metastatic breast cancer (MBC) remains open. ESR1 mutations might be of paramount importance, as they confer resistance to AI but not to SERD. In pts treated with first line palbociclib-AI combination (PADA-1 trial, NCT03079011), we investigated ESR1mut detection rate at inclusion, prior to any therapy, and their prognostic impact. Methods: The PADA-1 phase 3 trial (NCT03079011, UCBG-GINECO) evaluates the utility of monitoring the onset of ESR1mut in cell-free DNA (with a ddPCR assay [Jeannot et al, Oncogene 2020]) of pts receiving AI-palbociclib in first line. Included pts had no prior therapy for MBC and no overt resistance to AI. Results: N = 1017 ER+ HER2- MBC pts were included in 22 months from 04/2017 and had their cfDNA tested for ESR1mut at inclusion and during therapy. N = 33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), ESR1mut positivity being associated with a prior exposure to AI in the adjuvant setting (p < 0.01). N = 1 pt died after 1 month on treatment. In N = 25/32 evaluable pts (78%), ESR1mut became undetectable in cfDNA (AF < 0.1%) within the first 5 months on treatment, with a median time to ESR1mut ‘clearance’ of 34 days. Among these 25 pts, 14 pts (56%) had ESR1mut detected again during therapy; 2 pts (8%) experienced a progression with no ESR1mut detected; the remaining 9 patients (36%) were still both ESR1mut -free and progression-free at time of analysis. With a median FU time of 12.4 months (range: 0-25.3m) under AI-palbociclib, the 33 ESR1mut-positive pts had a shorter PFS (median: 17.5mo, 95%CI[10.5-NR]) than the 984 ESR1mut-negative pts (median not reached), with an estimated HR = 2.8 [1.6;5.0]. Updated data will be presented at the meeting. Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut under treatment and the observed 17.5 months-long median PFS both suggest that the AI-palbociclib combination retain a clinical activity in this population. ESR1mut-positivity prior was however associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. These findings may put into perspective the incoming results of the PARSIFAL trial. Clinical trial information: NCT03079011 .
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