Abstract
Mechanisms of dysfunctional T cell immunity in Hepatocellular Carcinoma (HCC) need to be well defined. B7 family molecules provide both co-stimulatory and co-inhibitory signals to T cells while tryptophan degrading enzymes like Indoleamine 2,3 dioxygenase (IDO) and Tryptophan 2,3 Dioxygenase (TDO) mediate tumor immune tolerance. It is necessary to identify their in situ correlative expression, which informs targets for combined immunotherapy approaches. We investigated B7 family molecules, IDO, TDO and immune responsive effectors in the tumor tissues of patients with HCC (n = 28) using a pathway-focused quantitative nanoscale chip real-time PCR. Four best correlative expressions, namely (1) B7-1 & PD-L2, (2) B7-H2 & B7-H3, (3) B7-2 & PD-L1, (4) PD-L1 & PD-L2, were identified among B7 family ligands, albeit they express at different levels. Although TDO expression is higher than IDO, PD-L1 correlates only with IDO but not TDO. Immune effector (Granzyme B) and suppressive (PD-1 and TGF-β) genes correlate with IDO and B7-1, B7-H5, PD-L2. Identification of the in situ correlation of PD-L1, PD-L2 and IDO suggest their cumulative immuno suppressive role in HCC. The distinct correlations among B7-1, B7-2, B7-H2, and B7-H3, correlation of PD-1 with non-cognate ligands such as B7-1 and B7-H5, and correlation of tumor lytic enzyme Granzyme B with IDO and PD-L2 suggest that HCC microenvironment is complexly orchestrated with both stimulatory and inhibitory molecules which together neutralize and blunt anti-HCC immunity. Functional assays demonstrate that both PDL-1 and IDO synergistically inhibit T cell responses. Altogether, the present data suggest the usage of combined immune checkpoint blocking strategies targeting co-inhibitory B7 molecules and IDO for HCC management.
Highlights
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities [1]
B7 family molecules are either co-stimulatory or co-inhibitory in stimulating and negating T-cell responses (Table 1). We have evaluated their relative expression in the hepatic tumor microenvironment in patients with HCC
Hierarchical organization of the cumulative median Cycle of Threshold (CT)−1 values identified the ranking of expression as values identified the ranking of expression from high to low as B7-H5, B7-H3, B7-H2, B7-1, PD-L1, B7-2, PD-L2, B7-H6, B7-H4, and B7-H7 (Figure 1A)
Summary
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities [1]. Defining the immunological mechanisms contributing to HCC pathogenesis in the intrahepatic tumor microenvironment is of translational interest [2]. Co-stimulatory, co-inhibitory (B7 family) pathways and enzymes of tryptophan degradation predominantly attenuate anti-tumor T-cell. B7 Family and IDO in HCC Ligand Receptor T Cell Fate B7-1 CD28 + CTLA4 B7-2 PD-L1 (B7-H1)
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