The Liver–Immunity Nexus and Cancer Immunotherapy

Lee, James C; Green, Michael D.; Huppert, Laura A; Chow, Christine; Pierce, Robert H.; Daud, Adil

doi:10.1158/1078-0432.ccr-21-1193

Cited by 66 publications

(44 citation statements)

References 82 publications

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“…There is also growing evidence that the liver is similarly immune privileged 37 , and our results confirm low immune cell features in liver metastases. Using this unique resource, we found that in 9/15 patients with multiple metastases, liver metastases had the lowest immune cell features of any synchronous site of metastasis.…”

supporting

confidence: 82%

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Perou

García-Recio²,

Wheeler

et al. 2022

Preprint

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Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

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supporting

confidence: 82%

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Perou

García-Recio²,

Wheeler

et al. 2022

Preprint

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“…Finally, the immune system is the host's defense system against infection and disease. Meanwhile, immunotherapy is a new cancer treatment strategy, which has been widely used to treat various solid tumors, including gastrointestinal tumors and gynecological tumors (116,117). In recent years, m 6 A regulatory factors have been widely studied in tumor immunotherapy and immune evasion.…”

Section: Discussionmentioning

confidence: 99%

Emerging Roles of m6A RNA Methylation Regulators in Gynecological Cancer

Huang

Kong

et al. 2022

Front. Oncol.

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Gynecological cancers seriously affect the reproductive system of females; diseases include ovarian tumors, uterine tumors, endometrial cancers, cervical cancers, and vulva and vaginal tumors. At present, the diagnosis methods of gynecological cancer are insufficiently sensitive and specific, leading to failure of early disease detection. N6-methyladenosine (m6A) plays various biological functions in RNA modification and is currently studied extensively. m6A modification controls the fate of transcripts and regulates RNA metabolism and biological processes through the interaction of m6A methyltransferase (“writer”) and demethylase (“erasers”) and the binding protein decoding m6A methylation (“readers”). In the field of epigenetics, m6A modification is a dynamic process of reversible regulation of target RNA through its regulatory factors. It plays an important role in many diseases, especially cancer. However, its role in gynecologic cancers has not been fully investigated. Thus, we review the regulatory mechanism, biological functions, and therapeutic prospects of m6A RNA methylation regulators in gynecological cancers.

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“…For example, given the distinct immune contexture of each of the growth patterns, the choice of immunotherapy may need to be adapted to the growth pattern of the liver metastases. It is also unclear whether the clinically relevant systemic immunosuppressive effects of the presence of liver metastases, leading to reduced benefit from immune checkpoint inhibitors, may be growth pattern-dependent 88 . A better insight into the interaction of liver-metastatic cancer cells with the complex immune environment of the liver will contribute to understanding the biology of the HGPs 77 .…”

Section: Discussionmentioning

confidence: 99%

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives, and recent mechanistic insights

Latacz

Höppener

Bohlok

et al. 2022

Preprint

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The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep learning algorithms for whole slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting pre-clinical and clinical research perspectives.

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The Liver–Immunity Nexus and Cancer Immunotherapy

Cited by 66 publications

References 82 publications

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Emerging Roles of m6A RNA Methylation Regulators in Gynecological Cancer

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives, and recent mechanistic insights

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