Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors

Abstract

CD4 type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Using isolated cells from individuals with hepatocellular carcinoma (HCC; = 39) or liver metastases from colorectal cancer (LM-CRC; = 60) we identify a CD4FoxP3IL-13IL-10 T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 () and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention.

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…As a consequence, tumor-infiltrating Treg, 40 , 41 type 1 regulatory T cells 52 and probably other types of immune suppressor cells were also present in these assays. Therefore, the reported functional effects of checkpoint inhibitors on effector T cells in these assays may be partly indirect, mediated by effects of these antibodies on suppressor cells.…”

The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases

“…Highly suppressive Tr1 cells have been characterized in several types of tumors including Hodgkin's lymphoma, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC) and colorectal cancer (CRC) (reviewed in Dennis et al, 2013). Tr1 cell generation from naive CD4 + T cell precursors is promoted at tumor sites mainly through the action of immature DCs or tolerogenic pDCs, as shown in in vitro models of HNSCC, HCC, and CRC (Bergmann et al, 2008;Pedroza-Gonzalez et al, 2015). Tr1 cells represent up to 30% of the tumor-infiltrating lymphocyte subsets in CRC patients (Scurr et al, 2014).…”

State-of-the-art of regulatory dendritic cells in cancer

“…They have been found to promote immunosuppression by enhancing IL-10 secretion by CD4 + Foxp3 − T cells in human hepatocarcinoma (Pedroza-Gonzalez, et al, 2015), while their presence is associated with regulatory Th2 responses in breast cancer patients (Ghirelli, et al, 2015) and human melanoma (Aspord, Leccia, Charles, & Plumas, 2013), as well as Treg activity in human breast cancer (Sisirak, et al, 2013). Finally, plasmacytoid DCs contribute to tumor-induced immunosuppression by inducing CD8 + regulatory T cells in the human ovarian cancer microenvironment (Wei, et al, 2005).…”