Cancer Immunotherapy ‘Uniquely Suppressed’ by Liver Tumors
“Though cancer immunotherapy has become a promising standard-of-care treatment – and in some cases, perhaps a cure – for a wide variety of different cancers, it doesn’t work for everyone, and researchers have increasingly turned their attention to understanding why.
For example, doctors have noticed that patients who initially respond well to the immunotherapy drugs known as checkpoint inhibitors, such as those that target a protein called PD-1, can develop resistance to these therapies if their cancer has metastasized from its initial location to form additional tumors in the liver – even if their primary cancer is quite distant from the liver.
In a new study published Oct. 2 in Science Immunology, a UC San Francisco research team led by Hematology and Oncology Clinical Fellow James Lee, MD, MHS, used a unique mouse model to figure out how this happens.
Then, the researchers, including senior author Jeffrey Bluestone, PhD, adjunct professor of microbiology and immunology and the A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology, showed that adding a second type of checkpoint inhibitor in a combination therapy can overcome this resistance, and might significantly increase the effectiveness of immunotherapy in patients with liver metastases.
The liver actually triggers differences in immune cells at distant sites,” Lee said. And what’s more, he added, “the liver can choose its enemy – what it wants to protect or not protect.”
https://www.ucsf.edu/news/2020/10/41865 ... ver-tumors
Cancer Immunotherapy ‘Uniquely Suppressed’ by Liver Tumors
Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis
“In a new study published Oct. 2 in Science Immunology, a UC San Francisco research team led by Hematology and Oncology Clinical Fellow James Lee, MD, MHS, used a unique mouse model to figure out how this happens.”
Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis
Salvage immunotherapy after liver metastases
Checkpoint blockade immunotherapy with anti–PD-1 is less effective in patients with cancer who have tumors that have metastasized to the liver. To unravel the mechanistic basis of suppressed antitumor immunity in this patient group, Lee et al. developed a preclinical mouse model in which liver tumors led to antigen-specific suppression of systemic immunity to extrahepatic tumors. Suppressed tumor immunity was associated with CTLA-4hi Tregs responsible for inducing myeloid-derived suppressor cells. Depletion of tumor-resident Tregs by anti–CTLA-4 treatment or functional inactivation of Tregs by treatment with an EZH2 inhibitor rescued the therapeutic potential of PD-1 blockade. The findings from the mouse model provide a basis for pursuing translational studies of salvage immunotherapy approaches that combine anti–PD-1 with Treg-targeting agents in patients with cancer and hepatic metastases.
Abstract
Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti–PD-1 immunotherapy. The mechanism of liver metastases–induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (Tregs) and modulation of intratumoral CD11b+ monocytes. The dysfunctional immune state could not be reversed by anti–PD-1 monotherapy unless Treg cells were depleted (anti–CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding Treg and CD11b+ monocyte targeting agents in combination with anti–PD-1 to treat patients with cancer with liver metastasis.
https://immunology.sciencemag.org/content/5/52/eaba0759
Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis
Salvage immunotherapy after liver metastases
Checkpoint blockade immunotherapy with anti–PD-1 is less effective in patients with cancer who have tumors that have metastasized to the liver. To unravel the mechanistic basis of suppressed antitumor immunity in this patient group, Lee et al. developed a preclinical mouse model in which liver tumors led to antigen-specific suppression of systemic immunity to extrahepatic tumors. Suppressed tumor immunity was associated with CTLA-4hi Tregs responsible for inducing myeloid-derived suppressor cells. Depletion of tumor-resident Tregs by anti–CTLA-4 treatment or functional inactivation of Tregs by treatment with an EZH2 inhibitor rescued the therapeutic potential of PD-1 blockade. The findings from the mouse model provide a basis for pursuing translational studies of salvage immunotherapy approaches that combine anti–PD-1 with Treg-targeting agents in patients with cancer and hepatic metastases.
Abstract
Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti–PD-1 immunotherapy. The mechanism of liver metastases–induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (Tregs) and modulation of intratumoral CD11b+ monocytes. The dysfunctional immune state could not be reversed by anti–PD-1 monotherapy unless Treg cells were depleted (anti–CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding Treg and CD11b+ monocyte targeting agents in combination with anti–PD-1 to treat patients with cancer with liver metastasis.
https://immunology.sciencemag.org/content/5/52/eaba0759
Debbie
Liver immunology and its role in inflammation and homeostasis
Liver immunology and its role in inflammation and homeostasis
Abstract
The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear ‘dangerous’ stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.
https://www.nature.com/articles/cmi20163
Abstract
The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear ‘dangerous’ stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.
https://www.nature.com/articles/cmi20163
Debbie
Liver immunology and its role in inflammation and homeostasis
Inflammatory processes and liver homeostasis
The human liver is classically perceived as a non-immunological organ, required for metabolic activities, nutrient storage and detoxification. We now know that the liver is also an immunologically complex organ, responsible for the production of acute phase proteins, complement components, cytokines and chemokines, and contains large, diverse populations of resident immune cells.1, 2, 3 In healthy individuals, the liver is constantly bombarded by a stream of dietary and commensal bacterial products with inflammatory potential. These gut-derived molecules must be tolerated by the hepatic immune system, which, at the same time, is poised to respond to danger. In the healthy liver, constantly changing metabolic and tissue remodeling activity, combined with regular exposure to microbial products, results in persistent, regulated inflammation. These inflammatory processes act in a tightly controlled fashion and are stimulated to additional activity only when the liver is required to rid itself of hepatotropic pathogens, malignant cells or toxic products of metabolic activity. Failure to clear such dangerous stimuli and resolve inflammation, leads to chronic infection, autoimmunity or tumor growth. This is inevitably associated with chronic pathological inflammation and disrupted tissue homeostasis, which can progress to fibrosis, cirrhosis and liver failure.
Inflammation is essential to combat infection; however, inflammatory mechanisms also underpin normal physiological events in the healthy body, including embryonic implantation,4 fetal development,5 involution post-partum and tissue repair.6 In the liver, homeostatic inflammatory processes control hemodynamic changes, capillary permeability, leukocyte migration into tissues and secretion of inflammatory mediators. This homeostatic inflammation is tightly regulated and the activation of inflammatory processes is intimately linked to mechanisms that resolve inflammation and promote tissue regeneration (Figure 1). This controlled inflammation is essential to maintain tissue and organ homeostasis and yet, when dysregulated, drives pathology and organ damage (Figure 1). In this review, we demonstrate an emerging role for inflammation and inflammatory mediators in normal liver homeostasis, in regulating the liver immune system and in liver regeneration following various forms of liver damage. We propose that homeostatic inflammation should be viewed as a normal part of the healthy liver and that therapeutic strategies targeting liver disease be designed to restore these homeostatic inflammatory processes.
https://www.nature.com/articles/cmi20163
The human liver is classically perceived as a non-immunological organ, required for metabolic activities, nutrient storage and detoxification. We now know that the liver is also an immunologically complex organ, responsible for the production of acute phase proteins, complement components, cytokines and chemokines, and contains large, diverse populations of resident immune cells.1, 2, 3 In healthy individuals, the liver is constantly bombarded by a stream of dietary and commensal bacterial products with inflammatory potential. These gut-derived molecules must be tolerated by the hepatic immune system, which, at the same time, is poised to respond to danger. In the healthy liver, constantly changing metabolic and tissue remodeling activity, combined with regular exposure to microbial products, results in persistent, regulated inflammation. These inflammatory processes act in a tightly controlled fashion and are stimulated to additional activity only when the liver is required to rid itself of hepatotropic pathogens, malignant cells or toxic products of metabolic activity. Failure to clear such dangerous stimuli and resolve inflammation, leads to chronic infection, autoimmunity or tumor growth. This is inevitably associated with chronic pathological inflammation and disrupted tissue homeostasis, which can progress to fibrosis, cirrhosis and liver failure.
Inflammation is essential to combat infection; however, inflammatory mechanisms also underpin normal physiological events in the healthy body, including embryonic implantation,4 fetal development,5 involution post-partum and tissue repair.6 In the liver, homeostatic inflammatory processes control hemodynamic changes, capillary permeability, leukocyte migration into tissues and secretion of inflammatory mediators. This homeostatic inflammation is tightly regulated and the activation of inflammatory processes is intimately linked to mechanisms that resolve inflammation and promote tissue regeneration (Figure 1). This controlled inflammation is essential to maintain tissue and organ homeostasis and yet, when dysregulated, drives pathology and organ damage (Figure 1). In this review, we demonstrate an emerging role for inflammation and inflammatory mediators in normal liver homeostasis, in regulating the liver immune system and in liver regeneration following various forms of liver damage. We propose that homeostatic inflammation should be viewed as a normal part of the healthy liver and that therapeutic strategies targeting liver disease be designed to restore these homeostatic inflammatory processes.
https://www.nature.com/articles/cmi20163
The liver receives a blood supply from two sources. The first is the hepatic artery which delivers oxygenated blood from the general circulation. The second is the hepatic portal vein delivering deoxygenated blood from the small intestine containing nutrients.
Debbie