New Roads Open Up for Implementing Immunotherapy in Mesothelioma

Treatment options for malignant mesothelioma are limited, and the results with conventional therapies have been rather disappointing to this date. Chemotherapy is the only evidence-based treatment for mesothelioma patients in good clinical condition, with an increase in median survival of only 2 months. Therefore, there is urgent need for a different approach to battle this malignancy. As chronic inflammation precedes mesothelioma, the immune system plays a key role in the initiation of this type of tumour. Also, many immunological cell types can be found within the tumour at different stages of the disease. However, mesothelioma cells can evade the surveillance capacity of the immune system. They build a protective tumour microenvironment to harness themselves against the immune system's attacks, in which they even abuse immune cells to act against the antitumour immune response. In our opinion, modulating the immune system simultaneously with the targeting of mesothelioma tumour cells might prove to be a superior treatment. However, this strategy is challenging since the tumour microenvironment possesses numerous forms of defence strategies. In this paper, we will discuss the interplay between immunological cells that can either inhibit or stimulate tumour growth and the challenges associated with immunotherapy. We will provide possible strategies and discuss opportunities to overcome these problems

Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer

Myeloid-derived suppressor cells (MDSCs) play an important role in immune suppression and accumulate under pathologic conditions such as cancer and chronic inflammation. They comprise a heterogeneous population of immature myeloid cells that exert their immunosuppressive function via a variety of mechanisms. Immunoglobulin-like transcript 3 (ILT3) is a receptor containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can be expressed on antigen-presenting cells and is an important regulator of dendritic cell tolerance. ILT3 exists in a membrane-bound and a soluble form and can interact with a yet unidentified ligand on T cells and thereby induce T-cell anergy, regulatory T cells, or T suppressor cells. In this study, we analyzed freshly isolated peripheral blood mononuclear cells (PBMCs) of 105 patients with non-small cell lung cancer and 20 healthy controls and demonstrated for the first time that ILT3 is expressed on MDSCs. We show that increased levels of circulating MDSCs correlate with reduced survival. On the basis of ILT3 cell surface expression, an ILT3(low) and ILT3(high) population of polymorphonuclear (PMN)-MDSCs could be distinguished. Interestingly, in line with the immunosuppressive function of ILT3 on dendritic cells, patients with an increased proportion of PMN-MDSCs and an increased fraction of the ILT3(high) subset had a shorter median survival than patients with elevated PMN-MDSC and a smaller ILT3(high) fraction. No correlation between the ILT3(high) subset and other immune variables was found. ILT3 expressed on MDSCs might reflect a previously unknown mechanism by which this cell population induces immune suppression and could therefore be an attractive target for immune intervention

Myeloid-derived suppressor cells in B cell malignancies

Tumor cells use several mechanisms such as soluble immune modulators or suppressive immune cells to evade from anti-tumor responses. Immunomodulatory cytokines, such as transforming growth factor-beta, interleukin (IL)-10, and IL-35, soluble factors, such as adenosine, immunosuppressive cells, such as regulatory T cells, NKT cells and myeloid-derived suppressor cells (MDSCs), are the main orchestra leaders involved in immune suppression in cancer by which tumor cells can freely expand without immune cell-mediated interference. Among them, MDSCs have attracted much attention as they represent a heterogenous population derived from myeloid progenitors that are expanded in tumor condition and can also shift toward other myeloid cells, such as macrophages and dendritic cells, after tumor clearing. MDSCs exert their immunosuppressive effects through various immune and non-immune mechanisms which make them as potent tumor-promoting cells. Although, there are several studies regarding the immunobiology of MDSCs in different solid tumors, little is known about the precise characteristics of these cells in hematological malignancies, particularly B cell malignancies. In this review, we tried to clarify the precise role of MDSCs in B cell-derived malignancies