CD8+ T cells are essential for adaptive immunity against infection and tumors. Their ability to proliferate after stimulation is crucial to their functionality. Dendritic cells (DCs) are professional antigen-presenting cells that induce their proliferation. Here, we show that thapsigargin-induced LAD2 mast cell (MC) line-released products can impair the ability of monocyte-derived DCs to induce CD8+ T-cell proliferation and the generation of Th1 cytokine-producing T cells. We found that culture medium conditioned with LAD2 MCs previously stimulated with thapsigargin (thapsLAD2) induces maturation of DCs as determined by the maturation markers CD80, CD83, CD86, and HLA-DR. However, thapsLAD2-matured DCs produced no detectable TNFα or IL-12 during the maturation. In addition, although their surface expression of PD-L1 was comparable with the immature or TLR7/8-agonist (R848)-matured DCs, their TIM-3 expression was significantly higher than in immature DCs and even much higher than in R848-matured DCs. In addition, contrary to R848-matured DCs, the thapsLAD2-matured DCs only tended to induce enhanced proliferation of CD4+ T cells than immature DCs. For CD8+ T cells, this tendency was not even detected because thapsLAD2-matured and immature DCs comparably induced their proliferation, which contrasted with the significantly enhanced proliferation induced by R848-matured DCs. Furthermore, these differences were comparably recapitulated in the ability of the tested DCs to induce IFNγ- and IFNγ/TNFα-producing T cells. These findings show a novel mechanism of MC-mediated regulation of adaptive immune responses.

• MeSH
• Lymphocyte Activation * drug effects   immunology   MeSH
• Cell Differentiation * drug effects   MeSH
• Cell Line MeSH
• Hepatitis A Virus Cellular Receptor 2 metabolism   MeSH
• CD8-Positive T-Lymphocytes * immunology   drug effects   MeSH
• Cytokines metabolism   MeSH
• Dendritic Cells * immunology   drug effects   metabolism   MeSH
• Imidazoles pharmacology   MeSH
• Humans MeSH
• Mast Cells * immunology   drug effects   metabolism   MeSH
• Monocytes immunology   drug effects   metabolism   MeSH
• Cell Proliferation * drug effects   MeSH
• Thapsigargin * pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hepatitis A Virus Cellular Receptor 2 MeSH
• Cytokines MeSH
• HAVCR2 protein, human MeSH Browser
• Imidazoles MeSH
• Thapsigargin * MeSH

The immune checkpoint inhibitors have revolutionized cancer immunotherapy. These inhibitors are game changers in many cancers and for many patients, sometimes show unprecedented therapeutic efficacy. However, their therapeutic efficacy is largely limited in many solid tumors where the tumor-controlled immune microenvironment prevents the immune system from efficiently reaching, recognizing, and eliminating cancer cells. The tumor immune microenvironment is largely orchestrated by immune cells through which tumors gain resistance against the immune system. Among these cells are mast cells and dendritic cells. Both cell types possess enormous capabilities to shape the immune microenvironment. These capabilities stage these cells as cellular checkpoints in the immune microenvironment. Regaining control over these cells in the tumor microenvironment can open new avenues for breaking the resistance of solid tumors to immunotherapy. In this review, we will discuss mast cells and dendritic cells in the context of solid tumors and how these immune cells can, alone or in cooperation, modulate the solid tumor resistance to the immune system. We will also discuss how this modulation could be used in novel immunotherapeutic modalities to weaken the solid tumor resistance to the immune system. This weakening could then help other immunotherapeutic modalities engage against these tumors more efficiently.

• Keywords
• cellular checkpoint, dendritic cells, immunotherapy, mast cells,
• MeSH
• Dendritic Cells pathology   MeSH
• Immunotherapy MeSH
• Immune Checkpoint Inhibitors MeSH
• Humans MeSH
• Mast Cells * pathology   MeSH
• Tumor Microenvironment MeSH
• Neoplasms * pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Immune Checkpoint Inhibitors MeSH