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Liver Resection

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Liver resection is recommended to treat some types of cancer originating in the liver (hepatocellular cancer, bile duct cancer, and gallbladder cancer), and occasionally benign liver tumors that are causing pain or other problems. It may also be recommended to treat certain cases of cancer that started in other organs that have metastasized or spread to the liver (colorectal cancer, breast cancer, sarcomas, neuroendocrine cancers, and some other types).

The procedure removes the part of the liver with the tumor and some of the healthy liver tissue around it. This helps to keep the cancer from spreading to other parts of the body.

Up to three quarters of the liver can be removed as long as the rest is healthy and can continue performing normal liver functions, which are essential for life. If the liver is not healthy, such as cirrhosis from hepatitis B or C virus infection, less liver can be removed safely.

Liver Proteins Keep T Cells Out Of Tumors

When harnessing immune cells to fight cancer, researchers traditionally focused on T cells or natural killer cells circulating through the blood. However, the critical cell types coordinating this immune response may be hidden in unexpected organs. For the past five years, Gregory Beatty, an oncologist at the University of Pennsylvania, has suspected one organ in particular: the liver.

Hepatocytes, the workhorses of the liver, are known for filtering blood toxins and metabolizing nutrients, but they also release proteins that can signal to far-off immune cells. Some of these proteins make up a phenomenon known as the acute phase reaction: a tsunami of inflammatory molecules that course through the bloodstream in the hours after an infection to spur an immune response. Despite this core function of hepatocytes, "most immunologists do not think of the liver," said Cliona O'Farrelly, a researcher at Trinity College Dublin who has separately studied the role of the liver in immunity.

Evidence suggests that the liver is a potent player in cancer immunology, as liver metastases and high levels of certain liver-related immune proteins reduce patients' responses to immunotherapy.1,2 In a new study published in Nature Immunology, Beatty and his team further underscored the importance of the liver in anticancer immunity by showing that activation of a specific signaling pathway in hepatocytes reduced T cell infiltration into tumors outside the liver.3 This, in turn, led to worse cancer outcomes. These findings highlight the potential of using the liver to control the immune system's effective attack on a tumor.

"The liver is a new immune checkpoint for us to think about," Beatty said. "Finding ways to target that therapeutically holds a lot of promise."

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Beatty's team previously investigated patterns of immune molecule levels in hepatocytes during cancer, but they still wondered how these liver changes might parallel changes in the tumor itself that have consequences for long-term outcomes.4 For example, tumors with many T cells typically have better outcomes after treatment.5

In the new study, the researchers compared mice with varying numbers of T cells in their pancreatic tumors. They found that the livers of animals with high T cell infiltration in the tumors had lower levels of the immune transcription factor signal transducer and activator of transcription (STAT3). Moreover, when they measured the acute phase protein serum amyloid A (SAA) that is typically produced in the liver, its levels were lower in mice with high T cell infiltration. In a previous study, the researchers showed that these molecules promote liver metastases.4

To further elucidate the liver's role in this immune pathway, the team genetically reduced the production of these molecules specifically in hepatocytes. "Suddenly there were all these T cells in the tumors," Beatty said. "It was remarkable." With additional genetic experiments, the team determined that SAA signaled to the toll-like receptor 2 protein on another immune cell type that directs T cells to penetrate the tumors.

Motivated by these findings, Beatty wanted to know whether reduced levels of SAA could drive anticancer responses and survival. He partnered with Vinod Balachandran, an oncologist at Memorial Sloan Kettering Cancer Center, to genetically reduce SAA in mice with pancreatic tumors with few T cells. Compared to mice with normal SAA, the genetically modified animals had more T cells in their tumors and longer survival after surgery to remove the tumors. When the team looked at data from 25 people with pancreatic cancer, they found a similar pattern; those who survived longer after surgery had lower SAA levels than those who survived short-term.

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"Even though there's huge amounts written about SAA, we really don't actually know what its primary role is," said O'Farrelly, who was not involved in the study. "For this paper to give a whole other different role to SAA is utterly fascinating."

Although Beatty focused on pancreatic cancer and melanoma for this work, previous research from his group showed the importance of SAA in lung and colorectal cancers, suggesting that this protein could play a role in many types of cancer.4Andreas Bergthaler, an immunologist at the Center for Molecular Medicine in Vienna who was not involved in the research, believes that the study adds an important piece to the puzzle of the liver's immune capabilities. "It's a great example of delineating organ crosstalk," he said. 

However, Bergthaler knows from his own experience linking liver-produced proteins to antiviral T cell responses that it can be hard to nail down the operative proteins among the dozens involved in a given pathway.6 He hopes that future studies will show that interfering with the SAA protein or other elements of the STAT3 pathway slows cancer progression.

Finding these targets is Beatty's priority. Moreover, he recognizes that other conditions, such as cardiovascular disease and diabetes, can cause liver inflammation, so he hopes to study how those conditions may influence anticancer immunity.

"If we could come up with strategies that intervene in liver inflammation, we could change [the] outcomes for patients that are undergoing surgery," he said. "That could be a game changer for many patients."

References

1. Tumeh PC, et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res. 2017;5(5):417-424.2. Laino AS, et al. Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition. J Immunother Cancer. 2020;8(1):e000842.3. Stone ML, et al. Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins. Nat Immunol. 2024;25(5):755-763.4. Lee JW, et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature. 2019;567(7747):249-252.5. Bruni D, et al. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020;20(11):662-680.6. Lercher A, et al. Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function. Immunity. 2019;51(6):1074-1087.E9.

Study Highlights Increasing Global Health Burden Of Liver Cancer

The global burden of liver cancer is rising, and public health efforts for prevention, vaccination, and treatment to address underlying etiologies are needed, according to research presented at ASCO 2024.

Global liver cancer incidence and mortality increased significantly in recent decades, indicating a need for prevention strategies for the disease and its various known etiologies, according to an abstract presented at the 2024 American Society of Clinical Oncology annual conference, held May 31 through June 4, 2024, in Chicago, Illinois.1 

"The most common type of liver cancer in adults is hepatocellular carcinoma, which can be due to alcohol, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), or other causes. In children the most common type of liver cancer is hepatoblastoma," the study authors wrote. "Comprehensive and comparative estimation of liver cancer burden can inform policy decisions and public health interventions to reduce incidence, morbidity, and mortality."

With the global incidence and mortality due to liver cancer rising, preventive measures are key to reducing cases worldwide.Image credit: SewcreamStudio - stock.Adobe.Com

In the US, primary liver cancer and intrahepatic bile duct cancer were diagnosed in approximately 41,630 patients, and about 29,840 individuals died of these cancers.2 Since 1980, rates in the US have tripled, and mortality due to liver cancer has more than doubled. In certain areas of the world, liver cancer is substantially more common, and it is the most common form of cancer diagnosed in countries in sub-Saharan Africa and Southeast Asia.

The new study aimed to update liver cancer estimates, including hepatoblastoma, from 1990 to 2021 using estimation methods from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021).1 The measures included total liver cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs). Further, etiology proportions from meta-analyses of literature reviews were applied to the data.

Life expectancy estimates were used to determine YLL calculations, while YLDs and prevalence were determined by expected survival, disease impacts, and disability weights. DALYs were defined as the sum of YLLs and YLDs. The authors also noted that liver cancers under age 10 were attributed to hepatoblastoma.

There were an estimated 529,000 cases of liver cancer in 2021 (95% uncertainty interval [UI], 480,000-594,000), and 484,000 deaths due to liver cancer (95% UI, 437,000-538,000). These incidences and deaths contributed to an estimated 12,900,000 DALYs (95% UI, 11,600,000-14,400,000).

Overall, the estimated number of cases increased by 114.3% (95% UI, 87.0%-145.3%) from 1990 to 2021, with deaths increasing by 102.5% (95% UI, 76.4%-132.0%). In the same time frame, DALYs increased by 70.6% (95% UI, 48.7%-96.8%).

Liver cancer has several known etiologies and most often occurs in individuals who have chronic liver disease due to hepatitis virus infection or cirrhosis.3 Preventive measures such as hepatitis B vaccination or receiving treatment for chronic hepatitis B are key to mitigating liver cancer incidence. Reducing exposure to aflatoxin B1, a poison from a fungus that can grow on foods stored in hot, humid places and most commonly grows in sub-Saharan Africa, Southeast Asia, and China, is another preventive measure to reduce liver cancer risk.

Regarding the etiologies of liver cancer, except hepatoblastoma, 37.4% of estimated deaths in 2021 were attributed to liver cancer due to hepatitis B (95% UI, 32.6%-42.6%), 30.3% were liver cancer due to hepatitis C (95% UI, 26.3%- 34.8%), 19.1% were liver cancer due to alcohol (95% UI, 15.8%-22.8%), 8.5% were liver cancer due to NASH (95% UI, 6.9%-10.3%), and 4.3% were liver cancer due to other causes (95% UI, 3.6%-5.1%).1

"These GBD 2021 estimates provide comprehensive estimates of the substantial health burden of liver cancer, highlighting a continued need for public health efforts targeting prevention, vaccination, treatment, or behavioral change," the authors concluded.

References

1. Kocarnik JM, May M, Acheson A, et al. The global burden of primary liver cancer and underlying etiologies from 1990 to 2021. J Clin Oncol. 2024;42(suppl 16):Abstract 10573. Doi:10.1200/JCO.2024.42.16_suppl.10573

2. Key statistics about liver cancer. American Cancer Society. Updated January 17, 2024. Accessed June 11, 2024. Https://www.Cancer.Org/cancer/types/liver-cancer/about/what-is-key-statistics.Html

3. Liver cancer causes, risk factors, and prevention. National Cancer Institute. Updated May 15, 2024. Accessed June 11, 2024. Https://www.Cancer.Gov/types/liver/what-is-liver-cancer/causes-risk-factors

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