While B7-engaged CD28 delivers a phosphoinositide 3-kinase (PI3K)-dependent co-stimulatory signal for T cell activation, CTLA-4 triggers an inhibitory signal [112,113], which hampers TCR-mediated activation of signaling molecules [114]

While B7-engaged CD28 delivers a phosphoinositide 3-kinase (PI3K)-dependent co-stimulatory signal for T cell activation, CTLA-4 triggers an inhibitory signal [112,113], which hampers TCR-mediated activation of signaling molecules [114]. (PMN)-MDSC or monocytic (M)-MDSC, reflecting their similarities to neutrophils and monocytes, respectively [24] (Figure 1). The crosstalk between MDSCs and cancer cells is critical for tumor development [25]. MDSCs are recruited to and proliferate in the TME in response to the cytokines and chemokines present in the tumoral milieu [26]. Not surprisingly, the extent of infiltration of these cells within tumor tissues is associated with poor prognosis [27]. Once infiltrated in the TME, MDSCs support tumor growth, on the one hand, by enhancing angiogenesis and promoting metastasis [28] and, on the other, by inhibiting T cell functions through the production of immunosuppressive factors [25]. While not abundantly represented, (DCs) are a key component of the TME [29] (Figure 1). CASP3 As professional antigen presenting cells (APCs), DCs recognize dangerous cells and migrate to the draining lymph node, where they provide the co-stimulatory signals for anti-tumor CD8+ T-cell priming [30,31]. In line with the dual role of immune cells in the TME, DCs can also acquire an immunosuppressive phenotype that results in immune RG108 tolerance and tumor dissemination [32]. Factors released in the TME, such as vascular endothelial growth factor (VEGF) or tumor-derived RG108 mediators, can impair the antigen-presenting ability of DCs, eventually suppressing their anti-tumoral activities [33,34]. Furthermore, under the hypoxic conditions found in TME, DCs express receptors usually found on myeloid cells to trigger pro-inflammatory signals [35]. (NK) cells are a heterogeneous population of innate immune cells with inherent capabilities in both recognizing and killing cancer cells. The presence of NK cells in the TME correlates with disease outcome in a variety of cancers, emphasizing the critical role that NK cells play in anti-tumor immune responses [36] (Figure 1). However, as for the other cell types described above, various alterations were recently found in the NK cell phenotype, which alter their functions and contribute to immune evasion in cancer RG108 patients. While on the one hand, NKs kill malignant cells expressing ligands for NK-specific surface receptors, such as the natural killer group 2D (NKG2D) ligand MIC-A [37], on the other hand, they paradoxically select and promote the expansion of neoplastic clones that develop mutations, which reduce the expression of NK-receptor ligands, making them resistant to immune attack [36]. 3. Adaptive Immune Cells Adaptive immune cells are considered the most specific and potent weapons against foreign and dangerous molecules. However, notwithstanding their antigen selectivity, in specific settings, they can become dysfunctional or even extremely dangerous. This is clearly exemplified by autoimmune diseases, RG108 exacerbated cytokine storms as observed in COVID-19 patients [38], and cancer, where adaptive immune cells do not function correctly, thereby favoring the onset and development of pathologic conditions. Lymphocytes recruited to the TME, referred to as tumor-infiltrating lymphocytes (TILs), are a heterogeneous population of adaptive immune cells that include the Th1, Th2, Th17 and the recently identified Th9 subsets, regulatory T and B cells (Tregs and Bregs), CTLs and B lymphocytes [7,39,40,41]. Each plays a distinct role in cancer development. While the IL-2- and interferon gamma (IFN)-producing Th1 subset has been shown to play an essential role in the induction and persistence of antigen-specific CTLs, acting therefore as an anti-tumoral Th subset, the Th2 and Th17 subsets act as pro-tumoral subsets in a cytokine-dependent manner [39,42]. Of note, na?ve CD4+ T lymphocytes undergo polarization to Th subsets in response to a specific cytokine milieu, which in the TME is composed of a mixture of soluble factors belonging to pro- and anti-tumoral classes, with.