Podoplanin Positive Myeloid Cells Promote Glioma Development by Immune Suppression

Abstract

The dynamic and interactive tumor microenvironment is conceived as a considerable parameter in tumor development and therapy response. Implementing this knowledge in the development of future cancer treatments could provide novel options in the combat of highly aggressive and difficult-to-treat tumors such as gliomas. One compartment of the tumor microenvironment that has gained growing interest is the immune system. As endogenous defense machinery the immune system has the capacity to fight against cancer cells. This, however, is frequently circumvented by tumor cells engaging immune-regulatory mechanisms that disable tumor-directed immune responses. Thus, in order to unlock the immune system against cancer cells, it is crucial to characterize in great detail individual tumor-associated immune cell subpopulations and dissect whether and how they influence immune evasion. In this study we investigated the function of a tumor-associated myeloid cell subpopulation characterized by podoplanin expression on the development of high-grade glioma tumors. Here, we show that the deletion of podoplanin in myeloid cells results in increased (CD8 + ) T-cell infiltrates and significantly prolonged survival in an orthotopic transplantation model. In vitro co-cultivation experiments indicate a podoplanin-dependent transcriptional regulation of arginase-1, a well-known player in myeloid cell-mediated immune suppression. These findings identify podoplanin positive myeloid cells as one novel mediator of the glioma-induced immune suppression. Thus, the targeted ablation of podoplanin positive myeloid cells could be included in combinatorial cancer therapies to enhance immune-mediated tumor elimination.

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

“…CD3 + CD8 + and natural killer (NK) cells eradicate mutationally transformed cells generating MHC I-complexed tumor-specific antigens via cytotoxic CD3 + CD8 + T cells, effectively preventing the progression and promotion of carcinogenically-mutated cells [120]. Abnormalities of these mechanisms could contribute to tumor initiation, promotion, and progression [121][122][123]. MHC II-bearing immunologically active astroglia and/or microglia abundantly populate malignant cerebral, brainstem, cerebellar, and spinal cord glioblastomas and astrocytomas [124].…”

Identification and validation of poor prognosis immunoevasive subtype of muscle-invasive bladder cancer with tumor-infiltrating podoplanin + cell abundance

“…35 It was also reported that PDPN-deficient macrophages impaired the expression of Arg1, a phenotype marker for M2 macrophages. 15 Through comparing the immune contexture between PDPN + cells high and low infiltration groups, we found that PDPN + cell abundance identified the immune contexture with increased Tregs and M2 macrophage infiltration in MIBC which were both associated with immunosuppression leading to poor prognosis. 25,30 There is a growing recognition that molecular classification may predict tumor progression and provide information on effective therapeutic responsiveness, including ACT, ICK blockade therapies and targeted therapies.…”

“…13 Previous studies uncovered that PDPN + macrophages promoted lymphangiogenesis and lymphoinvasion in breast cancer 14 while PDPN + myeloid cells suppressed T cell infiltration in glioma. 15 Moreover, PDPN serves as a marker for nonpathogenic Th17 subset, negatively regulating Th17-mediated inflammation. 16 Recently, PDPN has been identified as a novel ICK expressing on CD8 + T cells and CD4 + T cells, which limits the survival of T cells and orchestrates an exhausted T cell phenotype.…”

Lymphatic Endothelial Cell Progenitors in the Tumor Microenvironment

“…These cells also co-expressed a monocytic marker CD14 considered as one of defining components of the MDSC signature. PDPN-positive myeloid cells in a mouse glioma model were also shown to possess immunosuppressive activity, and deletion of PDPN from these myeloid cells increased tumor influx of CD8 + cytotoxic T-cells [34]. This evidence collectively suggests that M-LECP, like many other tumor-infiltrating immune cells, suppress the anti-tumor activities of the host.…”