Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy

Abstract

Autophagy is a vital, physiological catabolic process for cell survival by which cells clear damaged organelles and recycle nutrients when homeostasis is maintained. Cancer is a complex disease with uncontrolled growth of cancer cells. Recent studies have suggested the role of autophagy in cancer. A complex relationship exists between autophagy and cancer, since autophagy can contribute to the survival or the destruction of malignant cells depending on the stage of tumor development. In this review, we describe in detail the mechanism underlying autophagy in cancer cells and the intricate involvement of the programmed cell death-1 (PD1) receptor with its ligand (PD-L1). The overexpression of PD-L1 receptors on cancer cell membranes has been observed in several types of cancers. The interaction of PD-L1 on cancer cells with PD1 on the surface of T-cells causes cancer cells to escape from the immune system by preventing the activation of new cytotoxic T-cells in the lymph nodes and subsequent recruitment to the tumor. In addition to its immunopathogenicity, PD1 has been related to autophagy. Reduction of this receptor due to treatment increases autophagy, therefore promoting the recycling of nutrients and clearance of toxic species, consequently promoting cell survival. In addition, PD-L1/PD1 engagement can induce autophagy in nearby T-cells due to a decrease in the amino acids tryptophan and arginine and due to the deprivation of nutrients such as glucose followed by a reduction in glucose metabolism. Resistance to cancer therapies is attributed to various pathways in oncogenesis including, inhibition of tumor suppressors, alteration of the tumor metabolic environment, and upregulation of autophagy. Here we explore the interaction between the immunosuppressive PD-L1/PD1 engagement and autophagy mechanisms, and evaluate the impact of inhibition of these pathways in augmenting antitumor efficacy.

Autophagy-related genes prognosis signature as potential predictive markers for immunotherapy in hepatocellular carcinoma

“…Thus, the autophagy process affects HCC macrophage infiltration, and the prognosis signature of ATGs can predict the PD-L1 therapeutic effect. And studies show that the combination of autophagy blocker and PD-L1 inhibitor has a significant anti-tumor effect compared with PD-L1 inhibitor alone (Robainas et al, 2017).…”

Immunotherapy in Advanced Non-Small Cell Lung Cancer

“…The goal of anti-PD-1/PD-L1 therapy is to disrupt the pathways to liberate deactivated T cells and resume normal immune response. 11…”

“…As the PD-1/PD-L1 and CTLA-4 pathways are independent of each other, the theory behind combining therapies is to allow the treatments to complement each other therapeutically and increase the number of patients who benefit from ICI. 11 CheckMate-227 investigated this theory and compared the effects of ipilimumab in combination with nivolumab to nivolumab plus chemotherapy, or chemotherapy alone in patients with metastatic or recurrent NSCLC. PD-L1 TPS and TMB were used to assess outcomes in patient subgroups (►Table 1).…”

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

“…Moreover, it is worth mentioning that certain new FDA‐approved drugs, namely, programmed cell death 1 ligand 1 (PD‐L1) inhibitors such as MeDi4736, atezolizumab, pembrolizumab, and nivolumab, are rising stars for autophagy modulation. PD‐L1 inhibitors not only enhance immunoreactions to tumors but also reduce glucose levels in cells, creating nutrient deficiency and thereby inducing autophagy …”

“…PD-L1 inhibitors not only enhance immunoreactions to tumors but also reduce glucose levels in cells, creating nutrient deficiency and thereby inducing autophagy. 280,281 On the basis targets of energy regulation, we can identify agents that regulate energy metabolism, such as insulin, adiponectin, and glucagon, during the process of autophagy and then change the balance of autophagy-associated chemical reactions. [282][283][284][285] Although the expression of ATGs and the formation of phagosomes are rarely influenced by these agents, they significantly change the speed and efficiency of autophagy.…”