Intratumoral accumulation of podoplanin-expressing lymph node stromal cells promote tumor growth through elimination of CD4<sup>+</sup> tumor-infiltrating lymphocytes

Hatzioannou, Aikaterini; Nayar, Saba; Gaitanis, Anastasios; Barone, Francesca; Anagnostopoulos, Constantinos; Verginis, Panayotis

doi:10.1080/2162402x.2016.1216289

Cited by 13 publications

(12 citation statements)

References 56 publications

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“…C57BL/6 mice were purchased from the Jackson Laboratory, and Atg5 ΔLysM mice were generated by crossing Solid tumor induction. Induction of solid tumors was performed as previously described (63). Briefly, C57BL/6, Atg5 ΔLysM , and Atg5 fl/fl mice were s.c. injected with 3 × 10 5 B16-F10 melanoma or LLC1 cells.…”

Section: Methodsmentioning

confidence: 99%

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells

Alissafi¹,

Hatzioannou²,

Mintzas³

et al. 2018

Journal of Clinical Investigation

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Myeloid-derived suppressor cells (MDSCs) densely accumulate into tumors and potently suppress antitumor immune responses, promoting tumor development. Targeting MDSCs in tumor immunotherapy has been hampered by lack of understanding of the molecular pathways that govern MDSC differentiation and function. Herein, we identify autophagy as a crucial pathway for MDSC-mediated suppression of antitumor immunity. Specifically, MDSCs in patients with melanoma and mouse melanoma exhibited increased levels of functional autophagy. Ablation of autophagy in myeloid cells markedly delayed tumor growth and endowed antitumor immune responses. Notably, tumor-infiltrating autophagy-deficient monocytic MDSCs (M-MDSCs) demonstrated impaired suppressive activity in vitro and in vivo, whereas transcriptome analysis revealed substantial differences in genes related to lysosomal function. Accordingly, autophagy-deficient M-MDSCs exhibited impaired lysosomal degradation, thereby enhancing surface expression of MHC class II molecules, resulting in efficient activation of tumor-specific CD4+ T cells. Finally, targeting of the membrane-associated RING-CH1 (MARCH1) E3 ubiquitin ligase that mediates the lysosomal degradation of MHC II in M-MDSCs attenuated their suppressive function, and resulted in markedly decreased tumor volume followed by development of a robust antitumor immunity. Collectively, these findings depict autophagy as a molecular target of MDSC-mediated suppression of antitumor immunity.

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Section: Methodsmentioning

confidence: 99%

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells

Alissafi¹,

Hatzioannou²,

Mintzas³

et al. 2018

Journal of Clinical Investigation

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“…Ectopic lymphoid-like structures formed by lymph-node stromal cells not only play an important role in the regulation of the inflammatory response (see Section 8), but also contribute to tumor development and progression. In this context, a recent report found that podoplanin-expressing lymph-node stromal cells promote melanoma growth in vivo by inhibiting anti-tumor specific CD4 + T-cell proliferation and inducing the death of tumor infiltrating CD4 + lymphocytes in a cell-contact-independent fashion [204]. This observation points to a novel role of podoplanin-expressing lymph node stromal cells in tumor immune evasion.…”

Section: Significance Of Podoplanin Expression In Cancermentioning

confidence: 97%

Podoplanin in Inflammation and Cancer

Quintanilla

Montero-Montero

Renart

et al. 2019

IJMS

168

182

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Podoplanin is a small cell-surface mucin-like glycoprotein that plays a crucial role in the development of the alveoli, heart, and lymphatic vascular system. Emerging evidence indicates that it is also involved in the control of mammary stem-cell activity and biogenesis of platelets in the bone marrow, and exerts an important function in the immune response. Podoplanin expression is upregulated in different cell types, including fibroblasts, macrophages, T helper cells, and epithelial cells, during inflammation and cancer, where it plays important roles. Podoplanin is implicated in chronic inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis, promotes inflammation-driven and cancer-associated thrombosis, and stimulates cancer cell invasion and metastasis through a variety of strategies. To accomplish its biological functions, podoplanin must interact with other proteins located in the same cell or in neighbor cells. The binding of podoplanin to its ligands leads to modulation of signaling pathways that regulate proliferation, contractility, migration, epithelial–mesenchymal transition, and remodeling of the extracellular matrix. In this review, we describe the diverse roles of podoplanin in inflammation and cancer, depict the protein ligands of podoplanin identified so far, and discuss the mechanistic basis for the involvement of podoplanin in all these processes.

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“…Podoplanin-expressed CAFs contribute the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib [ 62 ]. Podoplanin-expressed lymph node stromal cells enhance tumor growth in vivo by eliminating CD4 + tumor-infiltrating lymphocytes that limit the efficiency of tumor immunotherapy [ 63 ]. Many reports suggest that podoplanin promotes tumor and metastasis; however, there are several controversial reports that podoplanin expression in lung SCC correlates with lower incidence of lymph node metastasis and good prognosis [ 64 – 66 ].…”

Section: Pathological and Physiological Functions Of Podoplaninmentioning

confidence: 99%

Platelet-activating factor podoplanin: from discovery to drug development

Takemoto

Miyata

Fujita³

2017

Cancer Metastasis Rev

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Tumor cell-induced platelet aggregation facilitates hematogenous metastasis by promoting tumor embolization, preventing immunological assaults and shear stress, and the platelet-releasing growth factors support tumor growth and invasion. Podoplanin, also known as Aggrus, is a type I transmembrane mucin-like glycoprotein and is expressed on wide range of tumor cells. Podoplanin has a role in platelet aggregation and metastasis formation through the binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). The podoplanin research was originally started from the cloning of highly metastatic NL-17 subclone from mouse colon 26 cancer cell line and from the establishment of 8F11 monoclonal antibody (mAb) that could neutralize NL-17-induced platelet aggregation and hematogenous metastasis. Later on, podoplanin was identified as the antigen of 8F11 mAb, and its ectopic expression brought to cells the platelet-aggregating abilities and hematogenous metastasis phenotypes. From the 8F11 mAb recognition epitopes, podoplanin is found to contain tandemly repeated, highly conserved motifs, designated platelet aggregation-stimulating (PLAG) domains. Series of analyses using the cells expressing the mutants and the established neutralizing anti-podoplanin mAbs uncovered that both PLAG3 and PLAG4 domains are associated with the CLEC-2 binding. The neutralizing mAbs targeting PLAG3 or PLAG4 could suppress podoplanin-induced platelet aggregation and hematogenous metastasis through inhibiting the podoplanin–CLEC-2 binding. Therefore, these domains are certainly functional in podoplanin-mediated metastasis through its platelet-aggregating activity. This review summarizes the platelet functions in metastasis formation, the role of platelet aggregation-inducing factor podoplanin in pathological and physiological situations, and the possibility to develop podoplanin-targeting drugs in the future.

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Intratumoral accumulation of podoplanin-expressing lymph node stromal cells promote tumor growth through elimination of CD4⁺ tumor-infiltrating lymphocytes

Cited by 13 publications

References 56 publications

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells

Podoplanin in Inflammation and Cancer

Platelet-activating factor podoplanin: from discovery to drug development

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Intratumoral accumulation of podoplanin-expressing lymph node stromal cells promote tumor growth through elimination of CD4+ tumor-infiltrating lymphocytes

Cited by 13 publications

References 56 publications

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells

Podoplanin in Inflammation and Cancer

Platelet-activating factor podoplanin: from discovery to drug development

Contact Info

Product

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Intratumoral accumulation of podoplanin-expressing lymph node stromal cells promote tumor growth through elimination of CD4⁺ tumor-infiltrating lymphocytes