Hepatocellular carcinoma (HCC) is a leading causes of global cancer deaths and cases continue to rise worldwide. HCC is a challenging tumor to manage due to its resistance to conventional cancer therapies and the complex tissue microenvironment in which it often develops. For many years, the only approved medical therapy for HCC was the multikinase inhibitor Sorafenib that led to an improvement in median survival by only a few months. Fortunately, new agents are now showing promise in clinical trials but overall survival in HCC still remains poor.
In the majority of HCC patients, the tumor develops in a stromal network that is characterized by tissue remodelling, fibrosis, and an immune microenvironment that promotes tumor evasion. The rationale for targeting the immune system in HCC has recently had a major boost with the success seen in clinical trials with immune checkpoint blockers (ICBs) targeting PD-1/PDL1 axis and CTLA-4. Furthermore, we are now entering the era of successfully combining immune therapy and agents that target the tissue microenvironment (TME), with promising results in trials combining ICBs with anti-vascular endothelial growth factor (anti-VEGF) agents. These results should encourage researchers to continue to elucidate the molecular mechanisms that drive cellular cross talk in the tissue stroma of HCC using clinically relevant in vivo and in vitro models. We need to better define how T cells are suppressed in the TME of HCC but also the contribution of other innate and adaptive immune subsets. The HCC microenvironment is characterized by resident hepatic immune cells and those recruited from the peripheral circulation. There is gathering interest in cellular cross talk between these immune subsets with hepatic stromal cells including sinusoidal endothelial cells, fibroblasts, as well as neighboring malignant and non-malignant epithelial cells. Progress in this field should lead to novel immunotherapeutics which can be used in combination with pre-existing therapies.
This Research Topic aims to provide a comprehensive overview of the key pathways that suppress tumor specific immune responses in the TME in the context of HCC. We welcome the submission of Original Research, Mini-Review, Review, and Methods articles covering, but not restricted to, the following topics:
1. Pathways that re-program hepatic innate and adaptive immune subsets towards immunosuppressive phenotypes in HCC.
2. Cellular cross talk between immune cells and stromal cells that prevents tumor eradication in the fibrogenic microenvironment of HCC.
3. Novel in vitro and in vivo experimental models to recapitulate the immune microenvironment of HCC.
4. The mechanisms of recruiting peripheral immunosuppressive subsets to the TME in HCC.
5. The role of cellular intrinsic factors (e.g. metabolism, mutations) and extrinsic factors (e.g. exosomes, chemokines) in promoting an immunosuppressive microenvironment in HCC.
6. Novel interventional strategies to modulate the immune microenvironment of HCC aiming at improving the efficacy of conventional or immune-directed tumor therapies.
7. Immunomodulatory role of the TME in the early steps of malignant transformation to HCC
Hepatocellular carcinoma (HCC) is a leading causes of global cancer deaths and cases continue to rise worldwide. HCC is a challenging tumor to manage due to its resistance to conventional cancer therapies and the complex tissue microenvironment in which it often develops. For many years, the only approved medical therapy for HCC was the multikinase inhibitor Sorafenib that led to an improvement in median survival by only a few months. Fortunately, new agents are now showing promise in clinical trials but overall survival in HCC still remains poor.
In the majority of HCC patients, the tumor develops in a stromal network that is characterized by tissue remodelling, fibrosis, and an immune microenvironment that promotes tumor evasion. The rationale for targeting the immune system in HCC has recently had a major boost with the success seen in clinical trials with immune checkpoint blockers (ICBs) targeting PD-1/PDL1 axis and CTLA-4. Furthermore, we are now entering the era of successfully combining immune therapy and agents that target the tissue microenvironment (TME), with promising results in trials combining ICBs with anti-vascular endothelial growth factor (anti-VEGF) agents. These results should encourage researchers to continue to elucidate the molecular mechanisms that drive cellular cross talk in the tissue stroma of HCC using clinically relevant in vivo and in vitro models. We need to better define how T cells are suppressed in the TME of HCC but also the contribution of other innate and adaptive immune subsets. The HCC microenvironment is characterized by resident hepatic immune cells and those recruited from the peripheral circulation. There is gathering interest in cellular cross talk between these immune subsets with hepatic stromal cells including sinusoidal endothelial cells, fibroblasts, as well as neighboring malignant and non-malignant epithelial cells. Progress in this field should lead to novel immunotherapeutics which can be used in combination with pre-existing therapies.
This Research Topic aims to provide a comprehensive overview of the key pathways that suppress tumor specific immune responses in the TME in the context of HCC. We welcome the submission of Original Research, Mini-Review, Review, and Methods articles covering, but not restricted to, the following topics:
1. Pathways that re-program hepatic innate and adaptive immune subsets towards immunosuppressive phenotypes in HCC.
2. Cellular cross talk between immune cells and stromal cells that prevents tumor eradication in the fibrogenic microenvironment of HCC.
3. Novel in vitro and in vivo experimental models to recapitulate the immune microenvironment of HCC.
4. The mechanisms of recruiting peripheral immunosuppressive subsets to the TME in HCC.
5. The role of cellular intrinsic factors (e.g. metabolism, mutations) and extrinsic factors (e.g. exosomes, chemokines) in promoting an immunosuppressive microenvironment in HCC.
6. Novel interventional strategies to modulate the immune microenvironment of HCC aiming at improving the efficacy of conventional or immune-directed tumor therapies.
7. Immunomodulatory role of the TME in the early steps of malignant transformation to HCC
