Mast Cells and Dendritic Cells as Cellular Immune Checkpoints in Immunotherapy of Solid Tumors

Abstract

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.

Identification and validation of a dysregulated TME-related gene signature for predicting prognosis, and immunological properties in bladder cancer

“…A previous study showed that tumor-infiltrating mast cells colocalize with regulatory T cells, coincide with local reduction of MHC-I and CD8 T cells, and is associated with anti-PD-1 resistance, which can be reversed by c-kit inhibitor treatment. At present, some studies suggested that MCs possess enormous capabilities to shape the immune microenvironment ( 48 , 49 ) and are becoming a new player in the field of cancer immunotherapy, depletion of these cells or downregulation of their functions in the TME can help break tumor resistance to anti-PD-1 therapy ( 50 ). Accordingly, we speculate that the TME prognostic model may affect BC survival outcomes by reshaping the tumor immune microenvironment, such as altering ECM, CD8+ T cell and these above-mentioned immunosuppressive cells, etc.…”

Immune regulation and prognosis indicating ability of a newly constructed multi-genes containing signature in clear cell renal cell carcinoma

“…CD4( +) T memory cells have already been reported to confer vital functions on malignancy immune regulation, including participating in the activation of CD8 + T and NK killing cells, involving in the tumour immunological reactions [ 60 , 61 ]. And mast cells were reported to be able to not only influence tumor expansion via inducing angiogenesis and changing tumor extracellular matrix composition, but also could influence the infiltration and activity of dendritic cells, tumor-associated macrophages and lymphocytes, promoting pro-inflammatory reactions in tumor microenvironment [ 47 , 62 , 63 ]. The association between the signature and immune checkpoints expression as well as different immune cells infiltration, suggesting the stronger immunosuppressive environment in high-risk groups of patients comparing to low-risk group, highlighting the potential of this group to benefit from further clinical immunotherapy.…”

Stabilizing Tumor-Resident Mast Cells Restores T-Cell Infiltration and Sensitizes Sarcomas to PD-L1 Inhibition

“…This challenge calls for a sophisticated harnessing of immune cells, such as the tumor-resident mast cells (MC), whose biological function can be programmed. MCs infiltrate the TME with a not yet fully developed or matured phenotype that can be influenced by the surrounding milieu ( 22 ) to play a protumorigenic ( 23, 24 ) or an antitumorigenic role ( 25 ), which can involve interaction with CAFs ( 26 ). Upon activation, MCs release secretory granules containing mediators that influence adaptive immune responses, ECM remodeling, and angiogenesis ( 27–31 ).…”