Impact of immune tolerance mechanisms on the efficacy of immunotherapy in primary and secondary liver cancers

Abstract

The liver is a functionally unique organ with an immunosuppressive microenvironment. The liver is the sixth most common site of primary cancer in humans and is a frequent site of metastasis from other solid tumors. The development of effective therapies for primary and metastatic liver cancer has been challenging due to the complex metabolic and immune microenvironment of the liver. The liver tumor microenvironment (TME) in primary and secondary (metastatic) liver cancers is heterogenous and consists of unique immune and stromal cell populations. Crosstalk between these cell populations and tumor cells creates an immunosuppressive microenvironment within the liver which potentiates cancer progression. Immune checkpoint inhibitors (ICIs) are now clinically approved for the management of primary and secondary liver cancer and can partially overcome liver immune tolerance, but their efficacy is limited. In this review, we describe the liver microenvironment and the use of immunotherapy in primary and secondary liver cancer. We discuss emerging combination strategies utilizing locoregional and systemic therapy approaches which may enhance efficacy of immunotherapy in primary and secondary liver cancer. A deeper understanding of the immunosuppressive microenvironment of the liver will inform novel therapies and therapeutic combinations in order to improve outcomes of patients with primary and secondary liver cancer.

The hidden messengers: cancer associated fibroblasts—derived exosomal miRNAs as key regulators of cancer malignancy

“…According to the findings of published studies, the primary sources of CAFs are as follows: (1) resident fibroblasts ( O’Connor et al, 2023 ; Buechler and Turley, 2018 ); (2) bone marrow mesenchymal stem cells ( Liubomirski et al, 2019 ); (3) vascular adventitia and smooth muscle cells ( Zeltz et al, 2019 ); (4) endothelial cells ( Chu et al, 2022 ; Shinkawa et al, 2022 ); (5) human adipose tissue-derived stem cells ( Sato et al, 2023 ); (6) stationary pancreatic stellate cells ( Morgan et al, 2023 ) and hepatic stellate cells ( Yin et al, 2013 ; Wang S. S. et al, 2021 ; Sankar et al, 2023 ); and (7) cancer stem cells ( Najafi et al, 2019 ) ( Figure 1 ). Understanding the origins of different CAFs can shed light on their functions and phenotypes.…”

Enterosorption may contribute to the reactivation of anticancer immunity and be an effective approach to tumor growth control

“…The pessimistic scenario results in the transition of the acute protective inflammatory reaction into a chronic form. The microenvironment created by the tumor during this process promotes its progression and accumulating toxic metabolites and biologically active products block the activity of the innate immunity and adaptive immune response forming immune tolerance to tumor antigens ( 8 , 12 ). Nevertheless, as suggested by some experimental data this tolerance is not absolute and can be reversed either by removing the toxic blockade ( 11 ) or through modern technologies regulating antitumor T-cell activity by inhibiting the STAT3 pathway in tumor cells since STAT3 activity and increased levels are associated with poor cancer prognosis in patients ( 10 , 15 , 17 ).…”

“…Nevertheless, as suggested by some experimental data this tolerance is not absolute and can be reversed either by removing the toxic blockade ( 11 ) or through modern technologies regulating antitumor T-cell activity by inhibiting the STAT3 pathway in tumor cells since STAT3 activity and increased levels are associated with poor cancer prognosis in patients ( 10 , 15 , 17 ). More recent approaches employ immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA4-4), programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) and lymphocyte activation gene-3 (LAG-3) in T- cell signaling pathways ( 12 , 18 ).…”

“…Cancer cells use a variety of mechanisms allowing them to evade effective control by the immune system, leading to accelerated tumor growth and a fatal outcome. One of the main mechanisms by which a tumor gains undeniable advantages in confrontation with the immune system may be the development of metabolic stress due to the accumulation of toxic products in the blood and organs, both actively produced by tumor cells and resulting from their death ( 7 , 11 , 12 ). The result of this may be systemic immunosuppression, the loss of the ability to recognize tumor antigens and provide any effective resistance to its growth ( 7 , 11 ).…”

“…While T-cell tolerance to tumors remains a major barrier in cancer immunotherapy, combined strategies using vaccination together with agonists of co-stimulatory pathways and inhibitors of immunologic checkpoints are capable of overcoming tolerance and generating significant anti-tumor response ( 8 – 10 , 12 , 15 – 18 ). In particular, studies in genetically manipulated mice showed that various immune system components can modify or even eliminate carcinogen-induced and spontaneously arising cancers ( 9 , 15 , 16 ).…”