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Research background Globally, primary liver cancer is the seventh most common cancer and the second most common cause of cancer death
.
Hepatocellular carcinoma (HCC) is the dominant type of liver cancer, accounting for about 75% of all liver cancers, and intrahepatic cholangiocarcinoma (ICC) accounts for about 10%
.
Because liver cancer is usually at an advanced stage when it is diagnosed, the recurrence rate after partial resection is high, and only a few patients are eligible for transplantation
.
The activities of the immune system are mainly regulated by T cells
.
In the tumor microenvironment (TME), antigen-presenting cells (APC) process antigens and present them to T cell receptors (TCR), in addition to the activation of costimulatory signals, they participate in different stages of T cell response (Figure 1a)
.
Many cancers mainly evade the immune system by overexpression of inhibitory ligands that bind to inhibitory immune checkpoints (ICPs) on the surface of T cells, thereby evading T cell attack (Figure 1b)
.
Based on the above principles, ICPI was developed as a monoclonal antibody corresponding to ICP
.
Their main function is to block the inhibitory signal between tumor cells and immune cells, thereby improving anti-tumor efficacy
.
Figure 1.
T cell activation mechanism of liver cancer immune tolerance The liver is an organ mainly composed of liver parenchymal cells, which plays an important role in systemic immune regulation
.
Except for bile duct epithelial cells, most liver cells are non-parenchymal cells with immune function, such as hepatic stellate cells (HSC), macrophages, natural killer (NK) cells and T cells (Figure 2a)
.
The liver is also the main producer of immune-related molecules, including C-reactive protein (CRP) and soluble pattern recognition receptor (PRR)
.
Compared with other organs, the liver needs to maintain a high level of immune tolerance to maintain a steady state between eliminating intestinal pathogens and avoiding inflammation
.
Under pathological conditions such as inflammation, fibrosis and steatosis, the immune homeostasis of the liver is impaired
.
The increase in immunosuppressive cells, inhibitory cytokines and immune checkpoint molecules promotes the occurrence of cancer (Figure 2b)
.
In turn, tumors can induce the formation of an immunosuppressive microenvironment, thus forming a vicious circle
.
The following table is a summary of other cellular components in the immune microenvironment of liver cancer
.
Figure 2.
Inhibitory cytokines of liver and tumor immune microenvironment.
In TME of liver cancer, tumor cells and immune cells secrete a variety of immunosuppressive cytokines to induce immune tolerance, represented by TGF-β, IL-10 and VEGF ( Figure 3)
.
Galectin-1 and dipeptidyl peptidase-4 have attracted much attention in recent years as new inhibitory cytokines
.
Figure 3.
Immune cells and cytokine TGF-β in TME is a pleiotropic cytokine that regulates cell proliferation, migration and adhesion
.
It can inhibit anti-tumor immunity through a variety of ways, including inducing phenotypic immature DC, inducing CD4+ T cells to transform into Tregs, and inhibiting the functions of CD8+ T cells and NK cells
.
IL-10 is an inhibitory cytokine with a broad-spectrum anti-inflammatory effect
.
In TME of liver cancer, IL-10 can be secreted by DC, HSC, MDSCs and other cells
.
In addition to the impact on APC and the inhibition of antigen presentation and the expression of MHC II and CD80/CD86, CD80/CD86 can also directly damage T cell function and reduce pro-inflammatory cytokines, including IL-1, IL-6, IL-12, Tumor Necrosis Factor (TNF)
.
At present, it is generally believed that VEGF mainly plays a role in promoting angiogenesis, but it has been reported that VEGF can promote the infiltration of suppressive immune cells and the expression of immune checkpoint molecules in liver cancer TME
.
Dipeptidyl peptidase-4 (DPP4) or CD26 is a serine exopeptidase.
Recent studies have shown that the Snail/DPP4/CXCL10 axis is involved in HCC immunosuppression and anti-PD1 treatment resistance
.
It is reported that the transformation of neuropeptide Y (NPY) by DPP4 enhances the activation and function of NPY5 receptor (Y5R) in liver cancer
.
At present, many DPP4 inhibitors such as sitagliptin, vildagliptin and saxagliptin have been used clinically
.
It has been confirmed that the DPP4 inhibitor sitagliptin increases the concentration of the chemokine CCL11 and increases the migration of eosinophils to solid tumors
.
This mechanism also contributes to the efficacy of checkpoint inhibitor therapy
.
Immune checkpoint receptors There are many types of immune checkpoint receptors, among which CTLA-4, PD1, PD-L1/2, LAG-3, TIM-3 and TIGIT are more thoroughly studied (Figure 4)
.
The monoclonal antibodies corresponding to the five receptors have been developed, and some of them have been approved by the FDA, which has greatly benefited patients
.
Figure 4.
Summary of current immune checkpoint receptors and ligands The following table describes the characteristics of co-suppressive immune checkpoint receptors: ICPI is applied to hepatocellular carcinoma in melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma and blood In tumors, ICPI shows good efficacy, so it is recommended as a first-line drug in many guidelines
.
Due to the special conditions of liver cancer patients (most of them are combined with hepatitis, liver cirrhosis, low body reserve, liver decompensation, liver tumor microenvironment immunosuppression, etc.
), compared with the above-mentioned tumors with better curative effects, HCC responds to ICPI Poor
.
ICPI is still being studied in clinical trials as a drug for the treatment of liver cancer
.
Nevertheless, some published results indicate that ICPI still has broad prospects in the treatment of HCC
.
The following table shows the phase III clinical trials currently using ICPI monotherapy
.
The combination of ICPI in the treatment of ICPI is ineffective for at least 30% of liver cancer patients.
Therefore, understanding the resistance of PD1/PD-L1 mAb or other ICPI is essential to improve the prognosis
.
The resistance mechanisms include low immunogenicity of tumor antigens, low antigen presentation efficiency, production of exhausted T cells, insufficient contact of TIL with tumor antigens and ICPs, and short retention time of immune memory
.
Therefore, the following methods can be used alone or in combination to improve the efficacy of ICPI: (1) Therapies that release tumor antigens (radiotherapy or chemotherapy) trigger an adaptive immune response; (2) Inhibitors that block VEGF and TGF-β enhance the efficacy of DC Function; (3) ICPIs as an adjuvant treatment for liver cancer resection (preoperative downstage or postoperative consolidation); (4) Anti-OX40 drugs improve TME and clear Tregs and other immunosuppressive cells; (5) By targeting immunostimulatory molecules (such as CD40 or CD137) agonists enhance T cell function; (6) oncolytic viruses or RNA adjuvants enhance antigen presentation and T cell stimulation
.
The following table is the clinical phase III study of ICPIs in the treatment of HCC: The following table is the clinical study of ICPIs in the treatment of intrahepatic cholangiocarcinoma: other immune checkpoint treatments include costimulatory factors (B7-1 and B7-2), epigenetic targets and a target protein (e.
g.
eIF6) and the like
.
The editor concludes that most liver cancers are already at an advanced stage when they are diagnosed, and treatment options are very limited
.
Only some patients can receive surgical resection or liver transplantation
.
Immunotherapy represented by ICPI provides more possibilities for inoperable liver cancer patients
.
Evidence-based medicine data also show that ICPI monotherapy or combination therapy can improve the prognosis of patients with advanced liver cancer
.
The research and development of the new ICPI is proceeding rapidly
.
As of July 2021, more than 200 liver cancer ICPI clinical trials have been registered
.
Although ICPI has shown gratifying curative effects, the following problems remain to be resolved: (1) Due to factors such as genetic background, etiology, HCV/HBV infection, region, ethnicity and other underlying diseases, the heterogeneity of patients is very large, so the same drug is used The effect of different patients varies greatly
.
Therefore, when using ICPI, it is necessary to fully consider the individual differences of patients
.
For a certain ICPI, what are the characteristics suitable for the crowd? Can we find biomarkers with good sensitivity and specificity to distinguish patients who are sensitive or resistant to ICPI? (2) IrAE that may occur during ICPI treatment
.
How do we balance the risks and benefits of ICPI? (3) Can patients with recurrent cancer after liver transplantation use ICPI? If so, can the final outcome be improved? (4) Similar to the treatment of HCC, the first targeted drug for intrahepatic cholangiocarcinoma is also a tyrosine kinase inhibitor
.
However, the efficacy of ICPI on intrahepatic cholangiocarcinoma is not ideal, and further research is needed
.
Generally speaking, patients with liver cancer need individualized treatment, and various factors need to be considered
.
The successful development of ICPIs with better curative effects requires the joint efforts of hospitals, scientific research institutions, pharmaceutical companies, and patients, and the future can be expected! References Yimin Zheng, Siwei Wang, Jiabin Cai, Aiwu Ke, Jia Fan, The progress of immune checkpoint therapy in primary liver cancer,Biochimica et Biophysica Acta (BBA)-Reviews on Cancer,2021
.
Hepatocellular carcinoma (HCC) is the dominant type of liver cancer, accounting for about 75% of all liver cancers, and intrahepatic cholangiocarcinoma (ICC) accounts for about 10%
.
Because liver cancer is usually at an advanced stage when it is diagnosed, the recurrence rate after partial resection is high, and only a few patients are eligible for transplantation
.
The activities of the immune system are mainly regulated by T cells
.
In the tumor microenvironment (TME), antigen-presenting cells (APC) process antigens and present them to T cell receptors (TCR), in addition to the activation of costimulatory signals, they participate in different stages of T cell response (Figure 1a)
.
Many cancers mainly evade the immune system by overexpression of inhibitory ligands that bind to inhibitory immune checkpoints (ICPs) on the surface of T cells, thereby evading T cell attack (Figure 1b)
.
Based on the above principles, ICPI was developed as a monoclonal antibody corresponding to ICP
.
Their main function is to block the inhibitory signal between tumor cells and immune cells, thereby improving anti-tumor efficacy
.
Figure 1.
T cell activation mechanism of liver cancer immune tolerance The liver is an organ mainly composed of liver parenchymal cells, which plays an important role in systemic immune regulation
.
Except for bile duct epithelial cells, most liver cells are non-parenchymal cells with immune function, such as hepatic stellate cells (HSC), macrophages, natural killer (NK) cells and T cells (Figure 2a)
.
The liver is also the main producer of immune-related molecules, including C-reactive protein (CRP) and soluble pattern recognition receptor (PRR)
.
Compared with other organs, the liver needs to maintain a high level of immune tolerance to maintain a steady state between eliminating intestinal pathogens and avoiding inflammation
.
Under pathological conditions such as inflammation, fibrosis and steatosis, the immune homeostasis of the liver is impaired
.
The increase in immunosuppressive cells, inhibitory cytokines and immune checkpoint molecules promotes the occurrence of cancer (Figure 2b)
.
In turn, tumors can induce the formation of an immunosuppressive microenvironment, thus forming a vicious circle
.
The following table is a summary of other cellular components in the immune microenvironment of liver cancer
.
Figure 2.
Inhibitory cytokines of liver and tumor immune microenvironment.
In TME of liver cancer, tumor cells and immune cells secrete a variety of immunosuppressive cytokines to induce immune tolerance, represented by TGF-β, IL-10 and VEGF ( Figure 3)
.
Galectin-1 and dipeptidyl peptidase-4 have attracted much attention in recent years as new inhibitory cytokines
.
Figure 3.
Immune cells and cytokine TGF-β in TME is a pleiotropic cytokine that regulates cell proliferation, migration and adhesion
.
It can inhibit anti-tumor immunity through a variety of ways, including inducing phenotypic immature DC, inducing CD4+ T cells to transform into Tregs, and inhibiting the functions of CD8+ T cells and NK cells
.
IL-10 is an inhibitory cytokine with a broad-spectrum anti-inflammatory effect
.
In TME of liver cancer, IL-10 can be secreted by DC, HSC, MDSCs and other cells
.
In addition to the impact on APC and the inhibition of antigen presentation and the expression of MHC II and CD80/CD86, CD80/CD86 can also directly damage T cell function and reduce pro-inflammatory cytokines, including IL-1, IL-6, IL-12, Tumor Necrosis Factor (TNF)
.
At present, it is generally believed that VEGF mainly plays a role in promoting angiogenesis, but it has been reported that VEGF can promote the infiltration of suppressive immune cells and the expression of immune checkpoint molecules in liver cancer TME
.
Dipeptidyl peptidase-4 (DPP4) or CD26 is a serine exopeptidase.
Recent studies have shown that the Snail/DPP4/CXCL10 axis is involved in HCC immunosuppression and anti-PD1 treatment resistance
.
It is reported that the transformation of neuropeptide Y (NPY) by DPP4 enhances the activation and function of NPY5 receptor (Y5R) in liver cancer
.
At present, many DPP4 inhibitors such as sitagliptin, vildagliptin and saxagliptin have been used clinically
.
It has been confirmed that the DPP4 inhibitor sitagliptin increases the concentration of the chemokine CCL11 and increases the migration of eosinophils to solid tumors
.
This mechanism also contributes to the efficacy of checkpoint inhibitor therapy
.
Immune checkpoint receptors There are many types of immune checkpoint receptors, among which CTLA-4, PD1, PD-L1/2, LAG-3, TIM-3 and TIGIT are more thoroughly studied (Figure 4)
.
The monoclonal antibodies corresponding to the five receptors have been developed, and some of them have been approved by the FDA, which has greatly benefited patients
.
Figure 4.
Summary of current immune checkpoint receptors and ligands The following table describes the characteristics of co-suppressive immune checkpoint receptors: ICPI is applied to hepatocellular carcinoma in melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma and blood In tumors, ICPI shows good efficacy, so it is recommended as a first-line drug in many guidelines
.
Due to the special conditions of liver cancer patients (most of them are combined with hepatitis, liver cirrhosis, low body reserve, liver decompensation, liver tumor microenvironment immunosuppression, etc.
), compared with the above-mentioned tumors with better curative effects, HCC responds to ICPI Poor
.
ICPI is still being studied in clinical trials as a drug for the treatment of liver cancer
.
Nevertheless, some published results indicate that ICPI still has broad prospects in the treatment of HCC
.
The following table shows the phase III clinical trials currently using ICPI monotherapy
.
The combination of ICPI in the treatment of ICPI is ineffective for at least 30% of liver cancer patients.
Therefore, understanding the resistance of PD1/PD-L1 mAb or other ICPI is essential to improve the prognosis
.
The resistance mechanisms include low immunogenicity of tumor antigens, low antigen presentation efficiency, production of exhausted T cells, insufficient contact of TIL with tumor antigens and ICPs, and short retention time of immune memory
.
Therefore, the following methods can be used alone or in combination to improve the efficacy of ICPI: (1) Therapies that release tumor antigens (radiotherapy or chemotherapy) trigger an adaptive immune response; (2) Inhibitors that block VEGF and TGF-β enhance the efficacy of DC Function; (3) ICPIs as an adjuvant treatment for liver cancer resection (preoperative downstage or postoperative consolidation); (4) Anti-OX40 drugs improve TME and clear Tregs and other immunosuppressive cells; (5) By targeting immunostimulatory molecules (such as CD40 or CD137) agonists enhance T cell function; (6) oncolytic viruses or RNA adjuvants enhance antigen presentation and T cell stimulation
.
The following table is the clinical phase III study of ICPIs in the treatment of HCC: The following table is the clinical study of ICPIs in the treatment of intrahepatic cholangiocarcinoma: other immune checkpoint treatments include costimulatory factors (B7-1 and B7-2), epigenetic targets and a target protein (e.
g.
eIF6) and the like
.
The editor concludes that most liver cancers are already at an advanced stage when they are diagnosed, and treatment options are very limited
.
Only some patients can receive surgical resection or liver transplantation
.
Immunotherapy represented by ICPI provides more possibilities for inoperable liver cancer patients
.
Evidence-based medicine data also show that ICPI monotherapy or combination therapy can improve the prognosis of patients with advanced liver cancer
.
The research and development of the new ICPI is proceeding rapidly
.
As of July 2021, more than 200 liver cancer ICPI clinical trials have been registered
.
Although ICPI has shown gratifying curative effects, the following problems remain to be resolved: (1) Due to factors such as genetic background, etiology, HCV/HBV infection, region, ethnicity and other underlying diseases, the heterogeneity of patients is very large, so the same drug is used The effect of different patients varies greatly
.
Therefore, when using ICPI, it is necessary to fully consider the individual differences of patients
.
For a certain ICPI, what are the characteristics suitable for the crowd? Can we find biomarkers with good sensitivity and specificity to distinguish patients who are sensitive or resistant to ICPI? (2) IrAE that may occur during ICPI treatment
.
How do we balance the risks and benefits of ICPI? (3) Can patients with recurrent cancer after liver transplantation use ICPI? If so, can the final outcome be improved? (4) Similar to the treatment of HCC, the first targeted drug for intrahepatic cholangiocarcinoma is also a tyrosine kinase inhibitor
.
However, the efficacy of ICPI on intrahepatic cholangiocarcinoma is not ideal, and further research is needed
.
Generally speaking, patients with liver cancer need individualized treatment, and various factors need to be considered
.
The successful development of ICPIs with better curative effects requires the joint efforts of hospitals, scientific research institutions, pharmaceutical companies, and patients, and the future can be expected! References Yimin Zheng, Siwei Wang, Jiabin Cai, Aiwu Ke, Jia Fan, The progress of immune checkpoint therapy in primary liver cancer,Biochimica et Biophysica Acta (BBA)-Reviews on Cancer,2021
