Intrahepatic immunoglobulin a complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of hepatocellular carcinoma

Background and Aims: Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment (TME). Immunoglobulin A (IgA) contributes to inflammation and dismantling anti-tumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in the TME of hepatocellular carcinoma (HCC). Approach and Results: CAF dynamics in HCC TME were analyzed via single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of advanced HCC patients treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels (p<0.05). Single-cell analysis showed that sub-cluster proportions in the CAF-fibroblast activation protein-alpha (FAP) matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of FAP in the CD68(+) cells from patients with high serum IgA levels (p<0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 (PD-L1) expression levels than those in mock-treated CAFs (p<0.05). Co-culture with CAFs attenuated cytotoxic function of activated CD8(+) T cells. Interestingly, activated CD8(+) T cells co-cultured with IgA-treated CAFs exhibited increased programmed death-1 (PD-1) expression levels than those co-cultured with mock-treated CAFs (p<0.05). Conclusions: Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T cell function. Our study highlighted their potential roles in tumor progression and immune suppression.