However, the latter will lead to on-targeted and off-tumor toxicity such as targeting the melanocyte antigens Melan-A (MART-1) or gp100 which may trigger autoimmune attack of normal tissue with melanocytes, such as skin, eye, and ear. trials proved a synergistic antitumor effect with the combination of targeted therapy and immunotherapy, implying a encouraging prospect for the treatment of metastatic melanoma. In order to achieve a better therapeutic effectiveness and reduce toxicity in patients, great efforts need to be made to illuminate multifaceted interplay between targeted therapy and immunotherapy. (62). These findings indicated downstream pathways of PD-1 are functionally redundant, which was possibly implemented by redundant phosphatases. Normally, this unfavorable opinions mechanism of PD-1/PD-L1 axis balances the immunity and immunopathology, thus to diminish tissue damage while limiting anti-tumor activity through immune evasion. PD-1 is usually usually highly expressed on activated or worn out T cells subsequent to prolonged exposure to high antigen loads. Typically, AM251 PD-L1 is usually upregulated on APCs or tumor cells which are capable of evading immune system surveillance, including metastatic melanoma cells (63, 64). PD-L1 is usually expressed on numerous cell types including T cells, B cells, NK cells, and tumor cells, the expression of which is usually driven by cytokines (IFN-) dependent and independent mechanisms, and the latter entails PTEN deletion, anaplastic lymphoma kinase (ALK) and EGFR mutation (65C67). Sometimes, the expression of PD-L1 is usually a biomarker for immunotherapy, whereas the expression of PD-L2 is largely confined to APCs. In addition to inhibiting the activation and other functions of T cells, PD-1 signaling may also regulate metabolic reprogramming, attenuate glycolysis and simultaneously promote lipid catabolism and fatty-acid oxidation, induce energy derivation, and partly lead to T cell exhaustion (68). PD-1 is usually a marker of effector T cells because it is usually expressed on all of the activated T cells, but not an exhaustion-specific molecule. PD-1 blockade can increase tumor rejection by reinvigorating T cell function, making it a predominant target for immunotherapy. It was another breakthrough of immune checkpoint blockade that nivolumab (BMS-936558) and pembrolizumab, two fully human anti-PD-1 monoclonal antibodies, were approved by FDA for the treatment of unresectable or metastatic melanoma in 2014. In a phase III trial, nivolumab dramatically improved PFS (5.1 vs. 2.2 months) and OS at 1 year (72.9 vs. 42.1%) compared with dacarbazine in metastatic melanoma without BRAF mutation. Besides, grade 3/4 adverse events were lower in nivolumab group (11.7%) than in dacarbazine group (17.6%) (69). As reported, drug-related adverse events with nivolumab were lower than those with ipilimumab (70). Similarly, pembrolizumab had better results in clinical outcomes than ipilimumab in advanced melanoma (71). Despite the dramatic progress in prognosis with monotherapy of PD-1 blockade, remission sustained only in a subset of patients. Therefore, it is crucial to selectively target this populace and develop effective combinatorial strategies for patients not benefiting from monotherapy. The expression of PD-L1 in tumors may be an indication for the prognosis (72, 73). Other parameters have also been pointed out, such as: (1) genetic signatures enrichment (metabolic signatures, mesenchymal, and suppressive inflammatory transcriptional phenotypes); (2) the presence and activity of TILs (more clonal T cell populace and less TCR diversity, transcriptional signature in which cytokine genes are increased); (3) general immune status of the patients (neutrophil to lymphocyte ratio and the frequency of circulating monocytes); (4) tumor foreignness HHIP (MSI-H tumors carry high mutational weight; neoantigens); (5) the presence of other inhibitory signaling within tumor cells (MDSCs, Tregs, inhibitory molecules) (74). Additionally, gut microbiome might regulate the response to PD-1 blockade immunotherapy in melanoma patients. More specifically, enrichment of family in gastrointestinal system is usually associated with a better prognosis (75). In order to maximize the clinical outcomes, combinatorial therapy is usually in need to further strengthen antitumor efficacy. Combination of anti-PD-1 with anti-CTLA-4 therapies significantly induced tumor regression in various malignancy types, including melanoma. According to AM251 a recent clinical trial, for PD-L1-positive melanoma patients with brain metastasis who received nivolumab plus ipilimumab, the intracranial clinical benefit rate was 57%, objective response rate was 55%, total response rate was 26%, with 6-, 9-, and 12-months survival of 92.3, 82.8, and 81.5%, respectively. Additionally, the incidence of immunotherapy-related adverse effects was not different from that of nivolumab or ipilimumab alone (76, 77). In addition to PD-1 blockade, anti-PD-L1 antibody has also been verified as an effective approach to improve antitumor effect by disrupting PD-1 signaling. As shown by Wang et al. the combination AM251 of diprovocim (TLR1/TLR2 agonist) and anti-PD-L1 eliminated melanoma completely in mice model by increasing TILs (78). Other Immune Checkpoint Blockades Apart from CTLA-4 and PD-L1, other immune checkpoints expressed on activated or worn out T cells include AM251 LAG-3, TIM-3, TIGIT, CD96, BTLA and CD160, which dampen T-cell effector function via diverse inhibitory signaling pathways. LAG-3 is similar to CD4 co-receptor in structure with greater affinity to MHC class II than CD4 (79). In addition to expression on activated T cells, LAG-3 was also found on the surface of NK.
However, the latter will lead to on-targeted and off-tumor toxicity such as targeting the melanocyte antigens Melan-A (MART-1) or gp100 which may trigger autoimmune attack of normal tissue with melanocytes, such as skin, eye, and ear
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