Tumor-mediated immune suppression of the sentinel lymph node (SLN) can hamper the development of an efficient anti-tumor immune response. Expression of inhibitory molecules on dendritic cell (DC) subsets that have migrated from the tumor region or that reside in these SLN, can negatively influence T cell priming and activation.
In two independent cohorts of tumor-negative SLN draining HPV-negative oral cavity squamous cell carcinomas, (n=9 USA and n=12 NL), we performed multi-parameter flow cytometry to map the immune suppressive microenvironment.
In both cohorts we observed that migratory Langerhans cells (LC) and interstitial DC (iDC) had an activated phenotype with high expression of co-stimulatory molecules, but this coincided with high expression of the immune checkpoint molecule PD-L1. In contrast, lymph node resident (LNR) DC subsets had an immature phenotype, scarce expression of PD-L1, but abundantly expressed the inhibitory molecule immunoglobulin-like transcript 4 (ILT4). ILT4 on tolerogenic dendritic cells (DC) has been described to result in induction of regulatory T cells (Treg). Indeed, increased expression of ILT4 (mean fluorescence index) on CD14- LNR-DC was found to correlate with increased frequencies of activated Treg (aTreg) in these SLN (Pearson r= 0.84, p<0.001). The same was true for expression of its ligand, HLA-G, on this subset (Pearson r=0.79, p<0.01).
Our data suggest that different DC subsets present in SLN draining HPV-negative HNSCC, may use different suppressive pathways to impair the generation of an effective anti-tumor immune response. It might thus take interference of both the PD-L1/PD-1 and the ILT-4/HLA-G pathways to effectively lift immune suppression and improve anti-tumor reactivity.