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18 pages, 3606 KiB

Open AccessArticle

Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression

by Matteo Ponzo, Anais Debesset, Mélissande Cossutta, Mounira Chalabi-Dchar, Claire Houppe, Caroline Pilon, Alba Nicolas-Boluda, Sylvain Meunier, Fabio Raineri, Allan Thiolat, Rémy Nicolle, Federica Maione, Serena Brundu, Carina Florina Cojocaru, Philippe Bouvet, Corinne Bousquet, Florence Gazeau, Christophe Tournigand, José Courty, Enrico Giraudo, José L. Cohen and Ilaria Cascone Show full author list Hide full author list

Cancers 2022, 14(17), 4265; https://doi.org/10.3390/cancers14174265 - 31 Aug 2022

Cited by 5 | Viewed by 2434 | Correction

Abstract

Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which [...] Read more.

Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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18 pages, 3254 KiB

Open AccessArticle

Immunomodulatory Responses of Subcapsular Sinus Floor Lymphatic Endothelial Cells in Tumor-Draining Lymph Nodes

by Eliane Sibler, Yuliang He, Luca Ducoli, Viviane Rihs, Patrick Sidler, Claudia Puig-Moreno, Jasmin Frey, Noriki Fujimoto, Michael Detmar and Lothar C. Dieterich

Cancers 2022, 14(15), 3602; https://doi.org/10.3390/cancers14153602 - 24 Jul 2022

Cited by 6 | Viewed by 2375

Abstract

Tumor-draining lymph nodes (LNs), composed of lymphocytes, antigen-presenting cells, and stromal cells, are highly relevant for tumor immunity and the efficacy of immunotherapies. Lymphatic endothelial cells (LECs) represent an important stromal cell type within LNs, and several distinct subsets of LECs that interact [...] Read more.

Tumor-draining lymph nodes (LNs), composed of lymphocytes, antigen-presenting cells, and stromal cells, are highly relevant for tumor immunity and the efficacy of immunotherapies. Lymphatic endothelial cells (LECs) represent an important stromal cell type within LNs, and several distinct subsets of LECs that interact with various immune cells and regulate immune responses have been identified. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize LECs from LNs draining B16F10 melanomas compared to non-tumor-draining LNs. Several upregulated genes with immune-regulatory potential, especially in LECs lining the subcapsular sinus floor (fLECs), were identified and validated. Interestingly, some of these genes, namely, podoplanin, CD200, and BST2, affected the adhesion of macrophages to LN LECs in vitro. Congruently, lymphatic-specific podoplanin deletion led to a decrease in medullary sinus macrophages in tumor-draining LNs in vivo. In summary, our data show that tumor-derived factors induce transcriptional changes in LECs of the draining LNs, especially the fLECs, and that these changes may affect tumor immunity. We also identified a new function of podoplanin, which is expressed on all LECs, in mediating macrophage adhesion to LECs and their correct localization in LN sinuses. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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17 pages, 2794 KiB

Open AccessArticle

Targeting HGF/c-Met Axis Decreases Circulating Regulatory T Cells Accumulation in Gastric Cancer Patients

by Juliette Palle, Laure Hirsch, Alexandra Lapeyre-Prost, David Malka, Morgane Bourhis, Simon Pernot, Elie Marcheteau, Thibault Voron, Florence Castan, Ariane Lacotte, Nadine Benhamouda, Corinne Tanchot, Eric François, François Ghiringhelli, Christelle de la Fouchardière, Aziz Zaanan, Eric Tartour, Julien Taieb and Magali Terme

Cancers 2021, 13(21), 5562; https://doi.org/10.3390/cancers13215562 - 5 Nov 2021

Cited by 7 | Viewed by 2924

Abstract

Elucidating mechanisms involved in tumor-induced immunosuppression is of great interest since it could help to improve cancer immunotherapy efficacy. Here we show that Hepatocyte Growth Factor (HGF), a pro-tumoral and proangiogenic factor, and its receptor c-Met are involved in regulatory T cells (Treg) [...] Read more.

Elucidating mechanisms involved in tumor-induced immunosuppression is of great interest since it could help to improve cancer immunotherapy efficacy. Here we show that Hepatocyte Growth Factor (HGF), a pro-tumoral and proangiogenic factor, and its receptor c-Met are involved in regulatory T cells (Treg) accumulation in the peripheral blood of gastric cancer (GC) patients. We observed that c-Met is expressed on circulating monocytes from GC patients. The elevated expression on monocytes is associated with clinical parameters linked to an aggressive disease phenotype and correlates with a worse prognosis. Monocyte-derived dendritic cells from GC patients differentiated in the presence of HGF adopt a regulatory phenotype with a lower expression of co-stimulatory molecules, impaired maturation capacities, and an increased ability to produce interleukin-10 and to induce Treg differentiation in vitro. In the MEGA-ACCORD20-PRODIGE17 trial, GC patients received an anti-HGF antibody treatment (rilotumumab), which had been described to have an anti-angiogenic activity by decreasing proliferation of endothelial cells and tube formation. Rilotumumab decreased circulating Treg in GC patients. Thus, we identified that HGF indirectly triggers Treg accumulation via c-Met-expressing monocytes in the peripheral blood of GC patients. Our study provides arguments for potential alternative use of HGF/c-Met targeted therapies based on their immunomodulatory properties which could lead to the development of new therapeutic associations in cancer patients, for example with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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18 pages, 1273 KiB

Open AccessArticle

Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors—A Retrospective, Real-World Cohort Study

by Maximilian Haist, Henner Stege, Saskia Pemler, Jaqueline Heinz, Maria Isabel Fleischer, Claudine Graf, Wolfram Ruf, Carmen Loquai and Stephan Grabbe

Cancers 2021, 13(20), 5103; https://doi.org/10.3390/cancers13205103 - 12 Oct 2021

Cited by 27 | Viewed by 2644

Abstract

Immune checkpoint inhibitors (ICI) significantly improved the prognosis of advanced melanoma patients. However, many patients do not derive long-term benefit from ICI therapy due to primary and acquired resistance. In this regard, it has been shown that coagulation factors contribute to cancer immune [...] Read more.

Immune checkpoint inhibitors (ICI) significantly improved the prognosis of advanced melanoma patients. However, many patients do not derive long-term benefit from ICI therapy due to primary and acquired resistance. In this regard, it has been shown that coagulation factors contribute to cancer immune evasion and might therefore promote resistance to ICI. In particular, recent observations in murine systems demonstrated that myeloid-derived factor Xa (FXa) impedes anti-tumor immunity in the tumor microenvironment and that the oral FXa inhibitor (FXa-i) rivaroxaban synergizes with ICI. The synergistic effect of FXa inhibitors with clinical ICI therapy is unknown. We performed a retrospective study of 280 metastatic melanoma patients who were treated with ICI and stratified them for concomitant anticoagulation (AC) by medical chart review. Data on baseline patient characteristics, specific AC treatment, ICI therapy, other tumor-targeting therapies, and clinical outcomes were analyzed. Of 280 patients who received ICI, 76 received concomitant AC during initial ICI therapy. Patients on AC were treated either with heparins (n = 29), vitamin K antagonists (VKA) (n = 20), or FXa-i (n = 27). Patients requiring AC during ICI therapy showed no significantly reduced objective response rate (ORR) (p = 0.27), or progression-free (PFS; median PFS 4 vs. 4 months; p = 0.71) or overall survival (OS; median OS: 39 vs. 51 months; p = 0.31). Furthermore, patients who underwent AC did not show significantly more bleeding complications (p = 0.605) than those who were not anticoagulated. Remarkably, stratification of patients by the class of AC revealed that patients receiving FXa-i were more likely to obtain CR (26.9 vs. 12.6%, p = 0.037), and showed better ORR (69.2 vs. 36.4%, p = 0.005), PFS (median PFS: 12 months vs. 3 months; p = 0.006), and OS (median OS not reached vs. 42 months; p = 0.09) compared to patients not receiving FXa-i. Patient demographics and tumor characteristics in this patient subcohort did not significantly differ from patients not on FXa-i. In summary, our study provides first clinical evidence that the clinical application of FXa-i may enhance the efficacy of ICI therapy via the restoration of anti-tumor immunity, while patients who received FXa-i were not more likely to encounter bleeding complications. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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Review

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22 pages, 2237 KiB

Open AccessReview

A Bloody Conspiracy— Blood Vessels and Immune Cells in the Tumor Microenvironment

by Lisa Terrassoux, Hugo Claux, Salimata Bacari, Samuel Meignan and Alessandro Furlan

Cancers 2022, 14(19), 4581; https://doi.org/10.3390/cancers14194581 - 21 Sep 2022

Cited by 3 | Viewed by 2023

Abstract

Cancer progression occurs in concomitance with a profound remodeling of the cellular microenvironment. Far from being a mere passive event, the re-orchestration of interactions between the various cell types surrounding tumors highly contributes to the progression of the latter. Tumors notably recruit and [...] Read more.

Cancer progression occurs in concomitance with a profound remodeling of the cellular microenvironment. Far from being a mere passive event, the re-orchestration of interactions between the various cell types surrounding tumors highly contributes to the progression of the latter. Tumors notably recruit and stimulate the sprouting of new blood vessels through a process called neo-angiogenesis. Beyond helping the tumor cope with an increased metabolic demand associated with rapid growth, this also controls the metastatic dissemination of cancer cells and the infiltration of immune cells in the tumor microenvironment. To decipher this critical interplay for the clinical progression of tumors, the research community has developed several valuable models in the last decades. This review offers an overview of the various instrumental solutions currently available, including microfluidic chips, co-culture models, and the recent rise of organoids. We highlight the advantages of each technique and the specific questions they can address to better understand the tumor immuno-angiogenic ecosystem. Finally, we discuss this development field’s fundamental and applied perspectives. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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21 pages, 1854 KiB

Open AccessReview

Angiogenesis Inhibitors and Immunomodulation in Renal Cell Cancers: The Past, Present, and Future

by Lawrence Kasherman, Derrick Ho Wai Siu, Rachel Woodford and Carole A. Harris

Cancers 2022, 14(6), 1406; https://doi.org/10.3390/cancers14061406 - 9 Mar 2022

Cited by 13 | Viewed by 3053

Abstract

Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due [...] Read more.

Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due to therapeutic resistance mechanisms, and there remains a need to develop novel therapeutic strategies. This article will review the synergistic mechanisms behind angiogenesis and immunomodulation in the tumor microenvironment and discuss the pre-clinical and clinical evidence for both clear-cell and non-clear-cell RCC, exploring opportunities for future growth in this exciting area of drug development. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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19 pages, 2262 KiB

Open AccessReview

Reductionist Three-Dimensional Tumor Microenvironment Models in Synthetic Hydrogels

by Rachel R. Katz and Jennifer L. West

Cancers 2022, 14(5), 1225; https://doi.org/10.3390/cancers14051225 - 26 Feb 2022

Cited by 7 | Viewed by 2287

Abstract

The tumor microenvironment (TME) plays a determining role in everything from disease progression to drug resistance. As such, in vitro models which can recapitulate the cell–cell and cell–matrix interactions that occur in situ are key to the investigation of tumor behavior and selecting [...] Read more.

The tumor microenvironment (TME) plays a determining role in everything from disease progression to drug resistance. As such, in vitro models which can recapitulate the cell–cell and cell–matrix interactions that occur in situ are key to the investigation of tumor behavior and selecting effective therapeutic drugs. While naturally derived matrices can retain the dimensionality of the native TME, they lack tunability and batch-to-batch consistency. As such, many synthetic polymer systems have been employed to create physiologically relevant TME cultures. In this review, we discussed the common semi-synthetic and synthetic polymers used as hydrogel matrices for tumor models. We reviewed studies in synthetic hydrogels which investigated tumor cell interactions with vasculature and immune cells. Finally, we reviewed the utility of these models as chemotherapeutic drug-screening platforms, as well as the future directions of the field. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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20 pages, 1816 KiB

Open AccessReview

The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer

by Irem Ozel, Inga Duerig, Maksim Domnich, Stephan Lang, Ekaterina Pylaeva and Jadwiga Jablonska

Cancers 2022, 14(3), 536; https://doi.org/10.3390/cancers14030536 - 21 Jan 2022

Cited by 32 | Viewed by 3835

Abstract

Angiogenesis, the formation of new blood vessels from already existing vasculature, is tightly regulated by pro- and anti-angiogenic stimuli and occurs under both physiological and pathological conditions. Tumor angiogenesis is central for tumor development, and an “angiogenic switch” could be initiated by multiple [...] Read more.

Angiogenesis, the formation of new blood vessels from already existing vasculature, is tightly regulated by pro- and anti-angiogenic stimuli and occurs under both physiological and pathological conditions. Tumor angiogenesis is central for tumor development, and an “angiogenic switch” could be initiated by multiple immune cells, such as neutrophils. Tumor-associated neutrophils promote tumor angiogenesis by the release of both conventional and non-conventional pro-angiogenic factors. Therefore, neutrophil-mediated tumor angiogenesis should be taken into consideration in the design of novel anti-cancer therapy. This review recapitulates the complex role of neutrophils in tumor angiogenesis and summarizes neutrophil-derived pro-angiogenic factors and mechanisms regulating angiogenic activity of tumor-associated neutrophils. Moreover, it provides up-to-date information about neutrophil-targeting therapy, complementary to anti-angiogenic treatment. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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