?(Fig

?(Fig.2).2). dyes. These agents can be useful for preclinical and clinical purposes and can overcome [18F]FDG limitations in discriminating between true-progression and pseudo-progression. This review provides a comprehensive overview of immune cells involved in microenvironment, available immunotherapies and imaging agents to highlight the importance Rabbit polyclonal to TUBB3 of new therapeutic biomarkers and their in vivo evaluation to improve the management of cancer patients. identification of antigen-specific immune response by PET imaging in patientsComparative study of CD34+ HPC-derived Langerhans cells versus monocyte-derived DCsMelanomaLangerhans cell-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than the monocyte-derived DC vaccinesType 1-polarized monocyte-derived DCsGliomaCombination of DC vaccination with polyICLC to trigger systemic inflammation driven by type I interferon family members Open in a separate window carcinoembryonic antigen; dendritic cell; interleukin-4; granulocyteCmacrophage colony-stimulating factor; human leukocyte antigen; HPC haematopoietic progenitor cell; natural killer cell; positron emission tomography; polyinosinicCpolycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose The availability of patient’s samples or specimens and the complex procedure of preparing individualized vaccines greatly limit the broad use of autologous cancer vaccines, including whole tumor cells or DCs [112]. Recombinant vaccines, which are based on peptides from defined tumor-associated antigens, and usually administered together with an adjuvant or an immune modulator, clearly have advantages. MAGE-1 is the first gene that was reported to encode a human tumor antigen recognized by T cells [123]. Most peptide-based vaccines in clinical trials target cancer-testis antigens, differentiation-associated antigens, or certain oncofoetal antigens (CEA, MUC-1) [112]. Although these vaccines were able to induce antigen-specific T cell responses, clinical outcomes have been disappointing; for example, in the phase III study that led to the approval of ipilimumab, no difference in overall survival was observed in patients with unresectable stage III or IV melanoma between the ipilimumab group and ipilimumab plus gp100 group [124]. However, Schwartzentruber et, al. in 2011, reported encouraging results from a randomized phase III trial involving Sorafenib (D3) patients with stage IV or locally advanced stage III Sorafenib (D3) cutaneous melanoma) in which Sorafenib (D3) the group treated with the gp100 (210M) peptide in Montanide ISA-51 adjuvant plus IL-2 demonstrated a statistically significant improvement in overall clinical response (16% vs. 6%, = 0.03), longer progression-free survival (2.2 months vs. 1.6 months, = 0.008) and improved median overall survival (OS = 17.8 vs. 11.1 months; = 0.06) compared with the IL-2 group [125]. Drugs inducing metabolic changes in the tumor microenvironment It is proposed that myeloid-derived suppressor cells (MDSCs) aberrantly infiltrate the TME and effectively promote T cell dysfunction through production of nitric oxide and reactive oxygen species and expression of indoleamine-2,3-dioxygenase (IDO) and arginase 1 in mice. In this context, IDO, a tryptophan-catabolizing enzyme plays a key role in the normal regulation of peripheral immune tolerance. This was first suggested when inhibition of IDO in pregnant mice caused spontaneous immune rejection of allogeneic foetuses [126]. In tumors, inhibition of the IDO pathway is theorized to help ameliorate a state of immune privilege created by tumor cells enhancing endogenous T cell mediated response against the tumor [127, 128]. The mechanism of cancer immunoediting is the direct consequence of a T cell-dependent immunoselection process that drives the formation of IDO1+ tumors [129]. IDO1 inhibitors could be administered as co-therapeutic agents in the presence of redox regulators, IFN-, or anti-IL-6. Combining IDO1 drugs with the inhibition of specific transcription factors regulating IDO1 activity (e.g., AhR) may also improve the effectiveness and specificity of chemotherapies. Current genome editing and exome sequencing technologies offer promising new strategies to identify novel tumor-specific mutational antigens and thus expand the repertoire of tumor-specific immunotherapies [129]. Cellular therapy of cancer Recently, the chimeric antigen receptor T (CAR-T) has been identified as a potential target in several malignancies. CAR-T cells recognize specific tumor antigens in a MHC-independent manner, which lead to the activation and execution of its antitumor function [130]. Once CAR specifically binds with tumor-associated antigens, T cells are activated through the phosphorylation of immune receptor tyrosine-based activation motifs and subsequently induce cytokine secretion, T cell proliferation, and cytotoxicity [131]. Chimeric immunoreceptor-activated T lymphocytes perform cytotoxicity through two predominant pathways: (1) secretion of perforin and granzyme granules and (2) activation of death receptor signalling via Fas/Fas-ligand or TNF/TNF-R [131]. Many strategies have been employed to potentiate the functions of CAR-T cells. It has been demonstrated that CAR-T cells with multiple signalling receptors could improve amplification, cytokine production, and cytotoxicity of T cells, as well as reduce antigen-induced cell death in vitro and in vivo [132]. Based on this mechanism, CAR-T antigens in solid.