PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome

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.

Excellent Response to Anti-PD-1 Therapy in a Patient with Hepatocellular Carcinoma Intolerant to Sorafenib

“…In recent years, immunotherapy in the form of immune checkpoint blockade has initiated a paradigm shift in cancer treatment [7]. Blockade of immune checkpoint pathways such as the programmed cell death receptor-1 (PD-1) pathway or the cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway can potentially offer a treatment strategy to reinstate host immune response against HCC and ultimately tumor regression [8].…”

Tumor hypoxia directed multimodal nanotherapy for overcoming drug resistance in renal cell carcinoma and reprogramming macrophages

“…These players are categorized based on their specific roles that include (i) RTK-mTOR that regulates critical tumorigenic signaling for tumor survival, immune suppression, and stroma formation [11], (ii) impairment of intrinsic and extrinsic apoptotic signaling is an essential player of drug resistance [12]. Induction of CARP-1 protein has been well documented to induce apoptosis in cancer cells under the conditions of serum withdrawal or therapy stress [10, 13]. (iii) CA IX is a tumor hypoxia marker for the maintenance of extracellular acidosis and cancer stemness, thus facilitating tumor growth and metastases.…”

“…Although, TKIs and mTOR inhibitors have increased therapeutic possibilities for treating RCC, a substantial proportion of patients do not respond adequately, and therapy resistance almost inevitably occurs. Recently, new strategies have also emerged that include immunotherapy such as PD-1 inhibitor (Nivolumab) [10] and the combination of chemo-immune therapy [11]. These developments suggest that combination treatments aimed at different, non-related pathways could be advantageous [12–14].…”

Immunological and Quality-of-Life Profiles in Women with Breast Cancer: Complementary versus Conventional Care

“…Recent therapies are, therefore, focused on breaking this tolerance using therapeutic monoclonal antibodies against molecules (called check-points of immunity) that decide activation versus tolerance of immune responses, for example PD-1, PD-L1, or CTLA-4 [23]. Humanized antibodies against these targets are used for treatment of several tumor types and are now evaluated in clinical trials including breast cancer [24]. In breast cancer, significantly higher blood CD8 + T cell frequencies, both total CD8 + cells and especially memory CD8 + cells, were observed in patients with metastatic (more aggressive) versus nonmetastatic (less aggressive) disease [25].…”