A research team of Canadian and French scientists, led by INRS professor Maya Saleh, studied resistance to immunotherapy in some patients with breast cancer. liver or hepatocellular carcinoma (HCC) associated with steatotic liver disease.
The results of the study were published in the journal Cell Reports.
Liver cancer: this is how new immunotherapies work.
Liver cancer is associated with known risk factors such as chronic hepatitis B or C infection, alcohol abuse, and metabolic dysfunction. It is the most common type of liver cancer. Despite great progress in the field of immunotherapy, this tumor is often fatal: approximately 75% of patients with advanced HCC do not respond to this type of treatment for reasons yet to be clarified.
This encouraged the research team to explore the link between liver disease associated with metabolic dysfunction, a chronic inflammatory liver disease, and therapeutic resistance to immunotherapy in patients with liver cancer.
“We have identified an immune biomarker for liver cancer associated with fatty liver disease, which will allow us to develop new immunotherapies,” explains Professor Maya Saleh, an international specialist in immuno-oncology. “We could envision immunotherapies that could restore an effective immune response against HCC by attenuating harmful liver inflammation.”
rLiver cancer remains a serious public health problem; in North America, its incidence has doubled in the last three decades. Before the approval of immunotherapy, treatment options for advanced HCC were limited and ineffective. For example, sorafenib improves median overall survival by only 3 months and is associated with significant side effects.
Immunotherapies, when given in combination, increase the average survival of liver cancer patients by an average of 17 months.
Thanks to the use of “omics” technologies, which allow large quantities of biological data to be analyzed in a short time, the team developed an immune map of adjacent non-tumorous liver cancer in 10 patients. These first immune maps led them to study databases of hundreds of patients in order to validate immune profiles related to risk factors and associated with disease severity.
These initial findings indicate that chronic inflammation from steatotic liver disease makes the liver cancer environment unique, with an expansion of immunosuppressive cells that cripple the tumor's immunologic attack.
The research team demonstrated that immunosuppressive cells express an inflammatory receptor called TREM1, which makes them more dangerous. Therefore, they highlighted TREM1 as a potential therapeutic target in HCC associated with steatotic liver disease.
By identifying this biomarker, which could explain treatment failure in people with HCC, the team pioneered a new approach to patient classification. This would allow them to determine who would be most likely to respond to immunotherapy before treatment even begins.
Such a scientific breakthrough would alleviate the psychological burden of patients who do not respond to immunotherapy. Major physical impacts, including side effects, could also be prevented.
“This is a promising avenue for the coming years. We will continue the analysis by characterizing the immune component of tumors in a larger cohort of patients, including comprehensive imaging of tumor cell composition and the use of artificial intelligence to link immune profiles to response to therapy. This could have a significant impact on the field,” concludes Professor Saleh.
Liver cancer is the fourth deadliest cancer in Hawaii, particularly affecting Native Hawaiian, Filipino and Japanese men. Patients can develop liver failure when tumors metastasize or spread to healthy parts of the liver, causing rapid decline in health and even death.
Immunotherapy is currently the standard of care for liver cancer patients. However, while newer immunotherapy drugs, which use a person's immune system to fight cancer, can slow the spread of many types of cancer, liver tumors often do not respond. Benjamin Green, a researcher at the University of Hawai'i Cancer Center, led a team to conduct research on public impact and published a study aimed at better understanding why this happens.
“Sometimes, immunotherapy can cause the generation of pro-cancer immune cells called regulatory T cells or 'Tregs,'” Green explained.
Using cutting-edge sequencing technology, Green and his team performed the most comprehensive analysis of liver Tregs to date in mice undergoing immunotherapy. They found that Tregs in the liver that expressed a CD29 protein were more immunosuppressive and increased in abundance when the mice were treated with immunotherapy.
Regardless of the type of cancer that was inserted into a mouse's liver, immunotherapy nearly doubled the amount of CD29+ Tregs. Although the CD29 protein is poorly studied in Tregs, it likely has an impact on the control of the Treg population in the liver.
“Our findings may be applicable to a range of liver diseases. In liver cancer, we believe CD29 may represent a potential new drug target to help patients respond to immunotherapy,” Green said. “We will decide whether these Tregs can be killed to improve liver cancer immunotherapy.”
Green is collaborating with data scientists and molecular pathologists at the UH Mānoa John A. Burns School of Medicine, as well as liver tumor doctors at Queen's Medical Center, to examine a series of liver tumors removed from Hawaiian and non-Hawaiian patients to see if they contain different percentages of CD29+ Tregs.
“I am grateful to the UH Cancer Center and the patients of Hawaii who have allowed me to continue this important research,” he said. “By working together, I believe we will help design more effective drugs for future liver cancer patients.”
Researchers at the Icahn School of Medicine at Mount Sinai have discovered a trio of immune cells within tumor niches associated with immunotherapy response in hepatocellular carcinoma (HCC). HCC is the primary type of liver cancer and one of the deadliest cancers worldwide. The findings, which help explain which patients benefit from immunotherapy and which do not, were described in Nature Medicine.
The researchers found that a specific niche of immune cells in tumors may be key to reactivating exhausted T cells and allowing them to attack liver tumors after treatment with checkpoint blockade. Also known as a PD1 inhibitor, checkpoint blockade is a type of cancer immunotherapy that can unleash the anti-tumor activity of T cells.
“Although checkpoint blockade has undoubtedly revolutionized cancer treatment, the majority of patients do not respond to this immunotherapy. Understanding at the molecular level why only some patients respond will help identify new targets to improve cancer treatment,” says study senior author Miriam Merad, M.D., Ph. .D., director of the Marc and Jennifer Lipschultz Precision Immunology Institute and director of the Human Immune Monitoring Center at Icahn Mount Sinai.
Researchers have designed a study that could benefit patients and provide new data to explore why immune cells in some patients can be reactivated by immunotherapy and eradicate tumors while the same treatment fails to help other patients.
This work follows a study recently published by our team in The Lancet Gastroenterology & Hepatology, which found that immunotherapy given before liver cancer surgery can kill tumors and likely residual tumor cells,” says Thomas Marron , M.D., Ph.D., head of the Early Phase Trial Unit at Mount Sinai Tisch Cancer Center, clinical trial manager and co-senior author of the study.
In this follow-up study, the research team analyzed tumor samples taken from 29 patients before and after treatment with checkpoint blockade. Using single-cell technology and powerful computational platforms, the team identified distinct groups of immune cells within tumors that determined which patients responded positively to immunotherapy and which did not.
These studies represent the first developments of Icahn Mount Sinai's TARGET “platform”: the neoadjuvant research group for the evaluation of therapies, founded by Drs. Marron and Merad. TARGET's goal is to leverage the technological capabilities of the Human Immune Monitoring Center and map the molecular changes that occur in cancer and immune cells undergoing treatment to precisely reveal how immunotherapy works.
Only by understanding how these breakthrough immunotherapies work in humans and the multiple mechanisms underlying treatment resistance can we further improve outcomes for all patients, the researchers say.
Reactivating a type of T cell called CD8 T cells by checkpoint blockade was known to be critical in eliminating tumor cells. Our new study shows that killer CD8 T cells are reactivated only when they are in proximity to two other types of immune cells: dendritic cells, which train CD8 T cells to recognize tumor cells, and helper CD4 T cells, which they help activate CD8 T cells,” says Alice Kamphorst, Ph.D., co-senior author of the study and assistant professor of Oncology Sciences at the Precision Immunology Institute.
These findings indicate that these specialized immune cell niches control CD8 T cell reactivation and subsequent tumor eradication by checkpoint blockade. By deciphering the molecules critical to the formation of these niches within tumors, the researchers aim to identify new therapeutic targets for use in combination with PD1 blockade and test these treatment combinations via the TARGET platform.
The article is titled: “Intratumoral dendritic cell helper T cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma.”
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