Correlation Patterns Among B7 Family Ligands and Tryptophan Degrading Enzymes in Hepatocellular Carcinoma

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.

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

“…One of the potential reasons for these discordances could be due to the involvement of other dominant immunoregulatory molecules that play along with PD-L1/PD1 pathway in HCC microenvironment ( Lafleur et al, 2018 ; Heinrich et al, 2020 ; Sharma and Motedayen Aval, 2021 ). Our recent work has identified that PD-L1 is the only molecule in B7 family which exhibits a high correlative expression with tryptophan degrading enzyme, IDO in HCC ( Chinnadurai et al, 2020 ). These findings suggest that IDO could play a role in protecting HCC cells from anti-tumor T cell immunity, which could be an explanation for the inconsistent efficacy of anti-PDL1/anti-PD-1 monotherapy.…”

“…There are many members present in the B7 family, namely, B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOSL), B7-H3, B7-H4 (B7x, B7S1), B7-H5, B7-H6, and B7-H7 which positively and negatively regulate T cell immunity ( Sharma and Allison, 2015 ; Schildberg et al, 2016 ; Ni and Dong, 2017a , b ). Our recent publication has demonstrated the correlation patterns of B7 family molecules in HCC microenvironment, which signifies the complex involvement of immunoregulatory molecules in modulating T cell immunity ( Chinnadurai et al, 2020 ). Tryptophan degrading enzymes, indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), play a significant role in conferring T cell suppression and confer tumor immune tolerance ( Munn and Mellor, 2016 ).…”

“…Tryptophan degrading enzymes, indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), play a significant role in conferring T cell suppression and confer tumor immune tolerance ( Munn and Mellor, 2016 ). Our recent publication has also demonstrated that IDO exhibits a strong correlative expression with PD-L1 in patients with HCC, which suggested that co-blocking of IDO and PD-L1 could be a promising strategy to promote anti-HCC T-cell immunity ( Chinnadurai et al, 2020 ). However, the regulation and functionality of B7 family molecules and tryptophan degrading enzymes in modulating HCC fate in the context of MSCs are unknown.…”

Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance

“… 9 , 10 , 11 , 12 IDO catalyzes the cleavage of tryptophan (Trp) in the rate-limiting step of the kynurenine (Kyn) pathway, resulting in the depletion of Trp and production of immunoregulatory molecules, including Kyn. 13 , 14 , 15 , 16 The IDO-induced production of Kyn and other metabolites in the tumor microenvironment could suppress the proliferation of functional T cells and natural killer cells while promoting the differentiation and activation of FoxP3 + (forkhead box P3 + ) regulatory T cells (Tregs). 17 , 18 Moreover, IDO activation correlates with poor clinical outcomes in patients with endometrial carcinoma, ovarian carcinoma and CRC.…”

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“…There are many members present in the B7 family, namely, B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOSL), B7-H3, B7-H4 (B7x, B7S1), B7-H5, B7-H6, and B7-H7 which positively and negatively regulate T cell immunity (Sharma and Allison, 2015;Schildberg et al, 2016;Ni and Dong, 2017a,b). Our recent publication has demonstrated the correlation patterns of B7 family molecules in HCC microenvironment, which signifies the complex involvement of immunoregulatory molecules in modulating T cell immunity (Chinnadurai et al, 2020). Tryptophan degrading enzymes, indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), play a significant role in conferring T cell suppression and confer tumor immune tolerance (Munn and Mellor, 2016).…”