Abstract
Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.
Highlights
Immunotherapy is an exciting approach, and tremendous strides have recently been made in our perception of the role of the host immune response in affecting tumor growth and response to various therapies (Pardoll, 2012)
Pembrolizumab is the first line treatment option for metastatic melanoma, metastatic non-small cell lung cancer (NSCLC; FIGURE 4 | (A) Innate immune resistance is driven by activation of PI3K/Akt kinase and IL-6/signal transducer and activator of transcription 3 (STAT3) oncogenic signaling that up-modulate PDL-1 protein expression in tumor cells, resulting programmed death receptor 1 (PD-1)/PD ligand 1 (PD-L1) complexation. (B) Adaptive immune resistance of cancer cells is outcome of INF-γ responded PDL1 expression
The development and antibody targeting of immune checkpoint mechanisms such as the PD-1/PD-L1 pathway has led to a clinically significant antitumor response
Summary
Immunotherapy is an exciting approach, and tremendous strides have recently been made in our perception of the role of the host immune response in affecting tumor growth and response to various therapies (Pardoll, 2012). Recent advancement has indicated that the expression of immune-inhibitory checkpoints such as PD-1/PD-L1 and CTLA-4 function as potent mediators for the balance and escape phases of cancer immune editing These molecules are expressed on activated T cells, but when they adhere to ligands either on APC (CTLA-4 binding to CD80/CD86) or tumor cells (PD-1 binding to PD-L1), they tend to suppress the antitumor response. PD-1 expression depends of tumor patient’s characteristics Immune response: The phase I studies with anti-PD-1 drugs, such as Nivolumab and Pembrolizumab with non-small-cell lung cancer, advanced melanoma, renal cell carcinoma, and other solid tumor patients have demonstrated very promising response with minimal side effects. Pembrolizumab is the first line treatment option for metastatic melanoma, metastatic non-small cell lung cancer (NSCLC; FIGURE 4 | (A) Innate immune resistance is driven by activation of PI3K/Akt kinase and IL-6/STAT3 oncogenic signaling that up-modulate PDL-1 protein expression in tumor cells, resulting PD-1/PD-L1 complexation.
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