T Cell Interferon and Cytotoxic Pathways in Axial Spondyloarthritis: Relationship to Secukinumab Response Profiles

Abstract

Our study aims to define the difference in granzyme (GZMs) expression in axial spondyloarthritis (axSpA) patients that predisposes secukinumab treatment response. Secukinumab treatment response, as determined using BASDAI50 scoring at week 24, stratified patients into responders (SEC-R) and nonresponders (SEC-NR). Multiome Sequencing was performed on CD4+ T cells from 3 SEC-R patients, 3 SEC-NR patients, and 2 healthy controls. SEC-R patients had an increased PU.1 CD4+ T cell cluster that had high expression of genes associated with the type 1 interferon (IFN) pathway. SEC-R patients have transcripts elevated in ATP synthesis and cytotoxic molecular functions. SEC-R patients have increased cytotoxic gene transcripts compared to SEC-NR patients. SEC-NR patients appear to have an altered TGFβ signaling pathway likely mediated through RELA and NFKB1. Although SEC-NR Tregs appears more responsive to TGFβ, there is higher expression of IFNγ genes in the Treg cluster compared to SEC-R. SEC-NR patients demonstrate enhanced IFNγ production that is dissociated from cytotoxic potential. This may occur due to increased SMAD7 activation of NFKB1 which prevents cells from differentiating into cytotoxic T cells and maintains a pro-inflammatory effector phenotype. Type 1 IFN is overrepresented in SEC-R patients before secukinumab treatment and elevated after treatment in SEC-NR patients. Regulation of type 1 interferons may therefore play an important role in influencing treatment response to secukinumab in axSpA.