Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase

Abstract

B7 family proteins serve as checkpoint molecules that protect tumors from T cell mediated lysis. Tryptophan degrading enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) also induce T cell immune tolerance. However, little is known about the relative contribution of B7 molecules, tryptophan degrading enzymes, as well as the impact of tumor and stromal cell interactions to the development of immunosuppressive tumor microenvironment. To investigate such interactions, we used a tripartite model of human hepatocellular carcinoma cell line (HepG2) and mesenchymal stromal cells (MSCs) co-cultured with peripheral blood mononuclear cells (PBMCs). Co-culture of HepG2 cells and activated PBMCs demonstrate that HepG2 cells undergo PBMC mediated cytolysis, despite constitutive expression of B7-H3 and upregulation of PD-L1 by IFNγ. Knockdown of B7-H3, PD-L1 or IDO does not modulate PBMC mediated lysis of HepG2 cells. However, TNFα preactivation enhances lysis of HepG2 cells, and blocking of TNFα production from PBMCs protects HepG2 cells. On the other hand, MSCs protect HepG2 cells from PBMC mediated lysis, even in the presence of TNFα. Further investigation showed that MSC mediated protection is associated with the unique secretome profile of upregulated and downregulated cytokines and chemokines. IFNγ activated MSCs are superior to TNFα activated or control MSCs in protecting HepG2 cells. Blockade of IFNγ driven IDO activity completely abolishes the ability of MSCs to protect HepG2 cells from cytolysis by PBMCs. These results suggest that inhibition of IFNγ activation of IDO induction in stromal cells, combined with usage of TNFα, could be a novel immunotherapeutic strategy to induce regression of hepatocellular carcinoma.

Sustained release of therapeutic gene by injectable hydrogel for hepatocellular carcinoma

“…As indicated design, the PBMC treatment was able to significant induce the apoptosis of tumor cells, and the combination with ABHD5 gene therapy demonstrated a synergistic effect on cell viability inhibition. The major cells of PBMC are lymphocytes, which including T cells, B cells and NK cells, the PD-1 expressing T cells contribute to the immunosuppression of PD-L1 positive tumors ( Chinnadurai et al, 2021 ; Liang et al, 2022 ; Pisani et al, 2022 ). ABHD5 was downregulated in liver tumor and showed a negative regulation on PD-L1 expression.…”

Effect of Co-culturing both placenta-derived mesenchymal stem cells and their condition medium in the cancer cell (HepG2) migration, damage through apoptosis and cell cycle arrest

“…It has been already observed that co-culturing both the adipose tissue derived msenchymal stem cell (AD-MSC) and the liver cancer cell inhibited the proliferation of the cancer cell through the upregulation of the p53 gene and also induced the apoptosis of the cancer cell line ( Serhal et al, 2019 ). The bone marrow derived msenchymal stem cells (BM-MSC) upon co-culture with the liver carcinoma cell line were shown to induce apoptosis by releasing cytokines ( Chinnadurai et al, 2021 ). The present study explained that hPMSCs and hPMSCs-CM had the ability to induce HepG2 cell cycle arrest.…”