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The tumor microenvironment of glioblastoma IDH-wildtype is highly immune suppressive and is characterized by a strong component of myeloid-derived suppressor cells (MDSCs). To interfere with the immune suppressive functions of MDSCs, a comprehensive understanding on how MDSCs acquire their suppressive phenotype is essential. Previously, we and others have shown a distinct Sialic acid-binding immunoglobulin-like lectin (Siglec) receptor expression profile for MDSCs in glioblastoma. Siglec receptors can transmit inhibitory signals comparable to PD-1 and are suggested to act as glyco-immune checkpoints. Here, we investigated how glioma specific Siglec-sialic acid interactions influence myeloid immune suppressive functions. Co-culturing monocytes with glioblastoma cells induced CD163 expression on the monocytes. Upon desialylation of the glioblastoma cells, this induction of CD163 was hampered, and furthermore, the monocytes were now able to secrete higher amounts of IL-6 and TNFα compared to fully sialylated glioblastoma cells. Additionally, Siglec-specific triggering using anti-Siglec-7 or Siglec-9 antibodies displayed a decreased TNFα secretion by the monocytes, validating the role of the Siglec–Sialic axis in the co-culture experiments. Together, our results demonstrate that glioblastoma cells induce a myeloid immune-suppressive phenotype that could be partly rescued by lowering the glioblastoma-associated sialic acid levels. This manuscript supports further research of the Siglec–Sialic acid axis in the context of glioblastoma and its potential to improve clinical outcome.

Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.

In situ tumor ablation techniques, like radiotherapy, cryo- and heat-based thermal ablation are successfully applied in oncology for local destruction of tumor masses. Although diverse in technology and mechanism of inducing cell death, ablative techniques share one key feature: they generate tumor debris which remains in situ. This tumor debris functions as an unbiased source of tumor antigens available to the immune system and has led to the concept of in situ cancer vaccination. Most studies, however, report generally modest tumor-directed immune responses following local tumor ablation as stand-alone treatment. Tumors have evolved mechanisms to create an immunosuppressive tumor microenvironment (TME), parts of which may admix with the antigen depot. Provision of immune stimuli, as well as approaches that counteract the immunosuppressive TME, have shown to be key to boost ablation-induced anti-tumor immunity. Recent advances in protein engineering have yielded novel multifunctional antibody formats. These multifunctional antibodies can provide a combination of distinct effector functions or allow for delivery of immunomodulators specifically to the relevant locations, thereby mitigating potential toxic side effects. This review provides an update on immune activation strategies that have been tested to act in concert with tumor debris to achieve in situ cancer vaccination. We further provide a rationale for multifunctional antibody formats to be applied together with in situ ablation to boost anti-tumor immunity for local and systemic tumor control.

Saponin-based adjuvants are being explored as vaccine components as they induce high levels of antigen cross-presentation, but it is unknown how. Here the authors show that these adjuvants enhance cross-presentation by driving production of lipid bodies inside CD11b dendritic cells.

Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3F(ax)-Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3F(ax)-Neu5Ac readily caused depletion of α2,3-/α2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3F(ax)-Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3F(ax)-Neu5Ac-treated cancer cells exhibited impaired binding to poly-l-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3F(ax)-Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy., (©2013 AACR.)