Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis

Comito, Giuseppina; Iscaro, Alessandra; Bacci, Marina; Morandi, Andrea; Ippolito, Luigi; Parri, Matteo; Montagnani, Ilaria; Raspollini, Maria Rosaria; Serni, Sergio; Simeoni, Luca; Giannoni, Elisa; Chiarugi, Paola

doi:10.1038/s41388-019-0688-7

Cited by 153 publications

(119 citation statements)

References 75 publications

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“…To date, it is widely accepted that cancer outcome does not only depend on the behavior of cancer cells, but also on the tumor microenvironment (TME) that coevolves with cancer cells, sustaining the enhancement of tumor malignancy. We previously demonstrated that cancer-associated fibroblasts (CAFs), the most represented stromal cells in the prostate TME, play an intriguing role during all stages of disease progression, including metastasis [14][15][16][17][18][19][20]. Herein, we show a selective action of WIN 55-212.2 mesylate, a synthetic cannabinoid with affinity for CB 1 and CB 2 higher than THC, on prostate cancer cell lines without affecting healthy counterpart.…”

Section: Introductionmentioning

confidence: 81%

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

Pietrovito

Iozzo

Bacci

et al. 2020

IJMS

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Endo-, phyto- and synthetic cannabinoids have been proposed as promising anti-cancer agents able to impair cancer cells’ behavior without affecting their non-transformed counterparts. However, cancer outcome depends not only on cancer cells’ activity, but also on the stromal cells, which coevolve with cancer cells to sustain tumor progression. Here, we show for the first time that cannabinoid treatment impairs the activation and the reactivity of cancer-associated fibroblasts (CAFs), the most represented stromal component of prostate tumor microenvironment. Using prostate cancer-derived CAFs, we demonstrated that WIN 55-212.2 mesylate, a synthetic full agonist of cannabinoid receptors (CBs) 1 and 2, downregulates α-smooth muscle actin and matrix metalloprotease-2 expression, and it inhibits CAF migration, essential features to ensure the activated and reactive CAF phenotype. Furthermore, by impairing stromal reactivity, WIN 55-212.2 mesylate also negatively affects CAF-mediated cancer cells’ invasiveness. Using selective antagonists of CBs, we proved that CAFs response to WIN 55-212.2 mesylate is mainly mediated by CB2. Finally, we suggest that endocannabinoids self-sustain both prostate tumor cells migration and CAFs phenotype by an autocrine loop. Overall, our data strongly support the use of cannabinoids as anti-tumor agents in prostate cancer, since they are able to simultaneously strike both cancer and stromal cells.

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Section: Introductionmentioning

confidence: 81%

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

Pietrovito

Iozzo

Bacci

et al. 2020

IJMS

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“…Conversely, Angelin A. et al demonstrated that the Treg transcription factor Foxp3 reprograms T cell metabolism, potentiating oxidative phosphorylation and suppressing Myc and glycolysis [112]. In line, Comito G. et al showed that CAFs-produced lactate reduces CD4 + Th1 population by SIRT1-mediated degradation of T-bet, and stimulates Treg proliferation by promoting FoxP3 activation in a prostate cancer model [113]. In addition, lactate acidosis has been negatively linked to T cell trafficking.…”

Section: Lactate and T Cellsmentioning

confidence: 99%

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Taddei

Pietrovito

Leo

et al. 2020

Cells

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Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

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“…Another example of T cell suppression caused by CAF metabolic reprogramming has recently been observed using CAFs derived from prostate cancer patients [ 72 ]. This study identifies glycolytic CAFs as a major source of extracellular lactate, at least in the context of prostate cancer, with the immunosuppressive effects of lactic acidosis on cytotoxic T cell activity within the TME being well documented [ 73 , 74 , 75 , 76 ].…”

Section: Caf-mediated Suppression Of T Cell Cytotoxic Functionmentioning

confidence: 99%

Cancer-Associated Fibroblast Mediated Inhibition of CD8+ Cytotoxic T Cell Accumulation in Tumours: Mechanisms and Therapeutic Opportunities

Freeman

Mielgo

2020

Cancers

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The tumour microenvironment (TME) is the complex environment in which various non-cancerous stromal cell populations co-exist, co-evolve and interact with tumour cells, having a profound impact on the progression of solid tumours. The TME is comprised of various extracellular matrix (ECM) proteins in addition to a variety of immune and stromal cells. These include tumour-associated macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells, as well as endothelial cells, pericytes and cancer-associated fibroblasts (CAFs). CAFs are the most abundant stromal cell population in many tumours and support cancer progression, metastasis and resistance to therapies through bidirectional signalling with both tumour cells and other cells within the TME. More recently, CAFs have been shown to also affect the anti-tumour immune response through direct and indirect interactions with immune cells. In this review, we specifically focus on the interactions between CAFs and cytotoxic CD8+ T cells, and on how these interactions affect T cell recruitment, infiltration and function in the tumour. We additionally provide insight into the therapeutic implications of targeting these interactions, particularly in the context of cancer immunotherapy.

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Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis

Cited by 153 publications

References 75 publications

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Cancer-Associated Fibroblast Mediated Inhibition of CD8+ Cytotoxic T Cell Accumulation in Tumours: Mechanisms and Therapeutic Opportunities

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