Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy

Tuccitto, Alessandra; Shahaj, Eriomina; Vergani, Elisabetta; Ferro, Simona; Huber, Veronica; Rodolfo, Monica; Castelli, Chiara; Rivoltini, Licia; Vallacchi, Viviana

doi:10.1007/s00428-018-2477-z

Cited by 45 publications

(30 citation statements)

References 121 publications

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“…The importance of stromal cells in the development of the tumor microenvironment and tumor progression is well known. However, little is known, regarding the ability of the cells from the microenvironment to reprogram their metabolism (12,13).…”

Section: Discussionmentioning

confidence: 99%

A combination of inhibitors of glycolysis, glutaminolysis and de�novo fatty acid synthesis decrease the expression of chemokines in human colon cancer cells

et al. 2019

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Lonidamine, 6-Diazo-5-oxo-L-norleucine (DON) and orlistat are well known inhibitors of glycolysis, glutaminolysis and of de novo fatty acid synthesis, respectively. Although their antitumor effects have been explored in detail, the potential inhibition of the malignant metabolic phenotype and its influence on the expression of chemokines and growth factors involved in colon cancer, have not been previously reported to the best of our knowledge. In the present study, dose-response curves with orlistat, lonidamine or DON were generated from cell viability assays conducted in SW480 colon cancer cells. In addition, the synergistic effect of these compounds was evaluated in SW480 human colon cancer cells. The determination of the doses used for maximum synergistic efficacy led to the exploration of the mRNA levels of the target genes hexokinase-2 (HK2), glutaminase-1 (GLS-1) and fatty acid synthase (FASN) in human SW480 and murine CT26.WT colon cancer cells. The cell viability was evaluated following transfection with small interfering (si)RNA targeting these genes and was assessed with trypan blue. The expression levels of chemokines and growth factors were quantified in the supernatant of SW480 cells with LEGENDplex™. The combination of lonidamine, DON and orlistat resulted in a synergistic cytotoxic effect and induced the transcription of the corresponding gene targets but their corresponding proteins were actually downregulated. The downregulation of the expression levels of HK2, GLS-1 and FASN following transfection of the cells with the corresponding siRNA sequences decreased their viability. The treatment significantly reduced the expression levels of 9 chemokines [interleukin-9, C-X-C motif chemokine ligand (CXCL) 10, eotaxin, chemokine ligand (CCL) 9, CXCL5, CCL20, CXCL1, CXCL11 and CCCL4] and one growth factor (stem cell factor). These changes were associated with decreased phosphorylated-nuclear factor κB-p65. The data demonstrate that lonidamine, DON and orlistat in combination reduce the expression levels of chemokines and growth factors in colon cancer cells. Additional research is required to investigate the exact way by which both tumor and stromal cells regulate the expression levels of chemokines and growth factors.

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Section: Discussionmentioning

confidence: 99%

A combination of inhibitors of glycolysis, glutaminolysis and de�novo fatty acid synthesis decrease the expression of chemokines in human colon cancer cells

et al. 2019

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“…In this regard, new strategies to overcome the immunosuppressive TME have been a major focus. These strategies include: (1) increasing TIL levels by abolishing the endothelial barrier, which prevents T-cell infiltration; forcing T-cell accumulation at the adjacent stroma and reducing their traffic into the tumour [43]; and (2) by eliminating the immunosuppressive TME to stimulate anti-tumour immunity [44]. Immune cells such as tumour-associated macrophages (TAM), MDSC, and Tregs can function to stimulate angiogenesis through secretion of VEGFA and PGE2, thus creating an endothelial barrier [45,46]; and promote immunetolerance via CTL and NK cell suppression [47][48][49][50].…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Law

Valdés-Mora

Gallego‐Ortega

2020

Cells

334

272

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The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.

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“…4,5 To identify the accurately predictive biomarkers, much focus has been on the biologic properties of cancer cells and immune response in their microenvironment. 6 Tumor-infiltrating lymphocytes (TILs) are a local histopathological reflection of the host's immune response against cancer cells. Currently, TILs have gained increasing attention in the treatment and prognosis prediction of melanoma.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis

et al. 2019

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Tumor-infiltrating lymphocytes (TILs) are associated with prognosis in various tumors. However, it remains controversial whether the presence of TILs is related to an improved prognosis in melanoma. This meta-analysis confirmed the favorable prognostic role of the CD3+, CD4+, CD8+, FOXP3+, and CD20 + TILs in the overall survival of melanoma patients and found an association between the TILs present and improved overall survival. Additionally, subgroup analysis demonstrated that brisk TILs were obviously associated with OS, RFS and DSS/MSS. Thus, TILs may be a predictive biomarker in melanoma. This analysis will provide more insight into the study of TILs and predictive biomarker.

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Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy

Cited by 45 publications

References 121 publications

A combination of inhibitors of glycolysis, glutaminolysis and de�novo fatty acid synthesis decrease the expression of chemokines in human colon cancer cells

A combination of inhibitors of glycolysis, glutaminolysis and de�novo fatty acid synthesis decrease the expression of chemokines in human colon cancer cells

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis

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