Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

Armitage, Jesse D.; Newnes, Hannah V.; McDonnell, Alison M.; Bosco, Anthony; Waithman, Jason

doi:10.3390/cells10010056

Cited by 16 publications

(16 citation statements)

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“…Immune effector cells in the TME can suppress tumor growth ( 19 ). However, tumor cells may escape immune surveillance, through various mechanisms such as polarizing monocytes and macrophages towards an M2 phenotype, creating tumor associated macrophages (TAMs), thereby suppressing cytotoxicity of antitumor immune cells ( 20 – 22 ). Although some of the immune infiltration cells including TAMs, natural killer cells, B cells, and regulatory T cells have no inhibitory effects on cancer cells, they influence the ability of tumors to escape immune attack ( 5 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

FUCA2 Is a Prognostic Biomarker and Correlated With an Immunosuppressive Microenvironment in Pan-Cancer

et al. 2021

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BackgroundThe expression of Fucosidase, alpha-L-2 (FUCA2) varies across tumors. However, its role in various tumor types and relationship with the tumor immune microenvironment (TIME) is poorly defined.MethodsWe analyzed profiles of FUCA2 expression using datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Next, gene alteration, clinical characteristics and prognostic values of FUCA2 were elucidated based on TCGA pan-cancer data. This was followed by gene set enrichment analysis by R software. Relationships between FUCA2 expression and immune infiltration and immune-related genes were also evaluated. Moreover, the association of immune cell infiltration with FUCA2 expression was evaluated across three different sources of immune cell infiltration data, namely the TIMER online, ImmuCellAI databases, as well as a published study. In addition, MTT assays was also conducted to validate the oncogene role of FUCA2 in lung cancer cells.ResultsFUCA2 was upregulated in most tumors, and this was significantly associated with poor survival rates. Gene set enrichment analysis uncovered that FUCA2 correlated with immune pathways in different tumor types. FUCA2 expression was positively related to tumor associated macrophages (TAMs), especially M2-like TAMs. Moreover, FUCA2 level showed a positive relationship with most immunosuppression genes, including programmed death-ligand 1 (PD-L1), transforming growth factor beta 1 (TGFB1), and interleukin-10 (IL10) in most cancer types. FUCA2 knockdown inhibited the cell viability in lung cancer cells.ConclusionsOur study reveals that FUCA2 is a potential oncogene and is indicative biomarker of a worse prognosis in pan-cancer. High FUCA2 expression may contribute to increased infiltration of TAMs and associates with an immunosuppressive microenvironment, providing a potential target for tumor therapy.

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Section: Discussionmentioning

confidence: 99%

FUCA2 Is a Prognostic Biomarker and Correlated With an Immunosuppressive Microenvironment in Pan-Cancer

et al. 2021

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“…In turn, therapies in which anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies were combined with therapies aimed at reducing the activity of immunosuppressive cytokines such as TGF-β (tumour growth factor beta), M-CSF (macrophage-colony stimulating factor), and IL-10 seem to be less effective [ 81 , 82 ]. Addition of drugs blocking IL-10 or TGF-β function to classical immunotherapy increased the risk of adverse effects in the form of autoimmune reactions [ 83 , 84 , 85 , 86 ]. Nevertheless, clinical trials are underway to investigate the effectiveness of M7824—a fusion protein consisting of a human IgG1 monoclonal antibody against PD-L1 fused to the extracellular domain of the receptor for TGF-β, which captures TGF-β in the tumour environment [ 86 ].…”

Section: Use Of Non-specific Immune System Stimulation and Tumour Microenvironment Modification In Immune Combination Therapiesmentioning

confidence: 99%

“…The tumour microenvironment has a very adverse effect on the immune system functioning therein [ 83 ]. An unfavourable tumour microenvironment results in exclusion of immune response outside the tumour.…”

Section: Use Of Non-specific Immune System Stimulation and Tumour Microenvironment Modification In Immune Combination Therapiesmentioning

confidence: 99%

Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

Wojas‐Krawczyk

Krawczyk

Gil

et al. 2021

Cancers

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Due to the limited effectiveness of immunotherapy used as first-line monotherapy in patients with non-small-cell lung cancer (NSCLC), the concepts of combining classical immunotherapy based on immune checkpoint antibodies with other treatment methods have been developed. Pembrolizumab and atezolizumab were registered in combination with chemotherapy for the treatment of metastatic NSCLC, while durvalumab found its application in consolidation therapy after successful chemoradiotherapy in patients with locally advanced NSCLC. Exceptionally attractive, due to their relatively low toxicity and high effectiveness, are treatment approaches in which a combination of two different immunotherapy methods is applied. This method is based on observations from clinical trials in which nivolumab and ipilimumab were used as first-line therapy for advanced NSCLC. It turned out that the dual blockade of immune checkpoints activated T lymphocytes in different compartments of the immune response, at the same time affecting the downregulation of immune suppressor cells (regulatory T cells). These experiments not only resulted in the registration of combination therapy with nivolumab and ipilimumab, but also initiated other clinical trials using immune checkpoint inhibitors (ICIs) in combination with other ICIs or activators of costimulatory molecules found on immune cells. There are also studies in which ICIs are associated with molecules that modify the tumour environment. This paper describes the mechanism of the synergistic effect of a combination of different immunotherapy methods in NSCLC patients.

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“…Like TAMS, MDSCs use a broad range of suppressive molecules to inhibit antitumor activity, including ARG1, iNOS, IDO, ROS, TGFβ and IL-10 [ 81 ]. We recently reviewed the dichotomous role these classically immune-suppressive molecules can play, focusing on both pro- and anti-tumoral effects in the TME [ 82 ]. In addition, it has been reported that MDSC can exert immunosuppressive effects via upregulation of PD-L1 [ 83 ], expression of the death receptor CD95 to induce T cell apoptosis [ 84 ] and production of MMP, which aid in tumour cell extravasation and migration [ 85 ].…”

Section: Cell Typesmentioning

confidence: 99%

“…Accordingly, many patients continue to respond poorly to standard of care therapies. It is well established that the immune system requires some degree of ‘fine-tuning’ to elicit effective and long-lasting anti-tumour immunity [ 82 ]. With the advancement of high-resolution omics technologies that encompass the global characterisation of DNA, RNA, chromatin accessibility, proteins and metabolites, new personalised treatment strategies can be developed to fine-tune these immune responses and improve individual patient outcomes ( Figure 1 ).…”

Section: Development Of Personalised Immunotherapies Guided By Integrated Omicsmentioning

confidence: 99%

Directing the Future Breakthroughs in Immunotherapy: The Importance of a Holistic Approach to the Tumour Microenvironment

Newnes

Armitage

Audsley

et al. 2021

Cancers

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Immunotherapy has revolutionised the treatment of cancers by exploiting the immune system to eliminate tumour cells. Despite the impressive response in a proportion of patients, clinical benefit has been limited thus far. A significant focus to date has been the identification of specific markers associated with response to immunotherapy. Unfortunately, the heterogeneity between patients and cancer types means identifying markers of response to therapy is inherently complex. There is a growing appreciation for the role of the tumour microenvironment (TME) in directing response to immunotherapy. The TME is highly heterogeneous and contains immune, stromal, vascular and tumour cells that all communicate and interact with one another to form solid tumours. This review analyses major cell populations present within the TME with a focus on their diverse and often contradictory roles in cancer and how this informs our understanding of immunotherapy. Furthermore, we discuss the role of integrated omics in providing a comprehensive view of the TME and demonstrate the potential of leveraging multi-omics to decipher the underlying mechanisms of anti-tumour immunity for the development of novel immunotherapeutic strategies.

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Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

Cited by 16 publications

References 311 publications

FUCA2 Is a Prognostic Biomarker and Correlated With an Immunosuppressive Microenvironment in Pan-Cancer

FUCA2 Is a Prognostic Biomarker and Correlated With an Immunosuppressive Microenvironment in Pan-Cancer

Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

Directing the Future Breakthroughs in Immunotherapy: The Importance of a Holistic Approach to the Tumour Microenvironment

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