Renin-angiotensin inhibitors reprogram tumor immune microenvironment: A comprehensive view of the influences on anti-tumor immunity

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Abstract

Renin-angiotensin system inhibitors (RASi) have shown potential anti-tumor effects that may have a significant impact in cancer therapy. The components of the renin-angiotensin system (RAS) including both, conventional and alternative axis, appear to have contradictory effects on tumor biology. The mechanisms by which RASi impair tumor growth extend beyond their function of modulating tumor vasculature. The major focus of this review is to analyze other mechanisms by which RASi reprogram the tumor immune microenvironment. These involve impairing hypoxia and acidosis within the tumor stroma, regulating inflammatory signaling pathways and oxidative stress, modulating the function of the non-cellular components and immune cells, and regulating the cross-talk between kalli krein kinin system and RAS.

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Mechanisms of resistance to immune checkpoint inhibitors

Russell Jenkins, David Barbie, Keith Flaherty (2018)

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors (‘targeted therapies’) largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data. Improved understanding of molecular and immunologic mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clinical and pre-clinical data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.

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Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies.

Kristin G Anderson, Ingunn Stromnes, Philip D. Greenberg (2017)

T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.

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Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues.

Craig Murdoch, Athina Giannoudis, Claire Lewis (2004)

The mechanisms responsible for recruiting monocytes from the bloodstream into solid tumors are now well characterized. However, recent evidence has shown that these cells then differentiate into macrophages and accumulate in large numbers in avascular and necrotic areas where they are exposed to hypoxia. This parallels their tendency to congregate in ischemic areas of other diseased tissues such as atherosclerotic plaques and arthritic joints. In tumors, macrophages appear to undergo marked phenotypic changes when exposed to hypoxia and to switch on their expression of a number of mitogenic and proangiogenic cytokines and enzymes. This then promotes tumor growth, angiogenesis, and metastasis. Here, we compare the various mechanisms responsible for monocyte recruitment into tumors with those regulating the accumulation of macrophages in hypoxic/necrotic areas. Because the latter are best characterized in human tumors, we focus mainly on these but also discuss their relevance to macrophage migration in ischemic areas of other diseased tissues. Finally, we discuss the relevance of these mechanisms to the development of novel cancer therapies, both in providing targets to reduce the proangiogenic contribution made by hypoxic macrophages in tumors and in developing the use of macrophages to deliver therapeutic gene constructs to hypoxic areas of diseased tissues.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 26 October 2018

Publication date (Electronic): 26 October 2018

Volume: 9

Issue: 84

Pages: 35500-35511

Affiliations

¹ Department of Surgery, Austin Health, University of Melbourne, Melbourne,VIC 3084, Australia

² Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC 3084, Australia

³ Department of Cardiology, Austin Health, University of Melbourne, Melbourne, VIC 3084, Australia

Author notes

Correspondence to: Dora L. Vallejo-Ardila, dvallejo@ 123456student.unimelb.edu.au

Article

Publisher ID: 26174

DOI: 10.18632/oncotarget.26174

PMC ID: 6231452

SO-VID: c0fd83d8-b1d9-42da-8c31-11d78016bb71

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Renin-angiotensin inhibitors reprogram tumor immune microenvironment: A comprehensive view of the influences on anti-tumor immunity

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Karger: Oncology

Most cited references 82

Mechanisms of resistance to immune checkpoint inhibitors

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies.

Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues.

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