Resistance Mechanisms of Anti-PD1/PDL1 Therapy in Solid Tumors

Abstract

In cancer-immunity cycle, the immune checkpoint PD1 and its ligand PDL1 act as accomplices to help tumors resist to immunity-induced apoptosis and promote tumor progression. Immunotherapy targeting PD1/PDL1 axis can effectively block its pro-tumor activity. Anti-PD1/PDL1 therapy has achieved great success in the past decade. However, only a subset of patients showed clinical responses. Most of the patients can not benefit from anti-PD1/PDL1 therapy. Furthermore, a large group of responders would develop acquired resistance after initial responses. Therefore, understanding the mechanisms of resistance is necessary for improving anti-PD1/PDL1 efficacy. Currently, researchers have identified primary resistance mechanisms which include insufficient tumor immunogenicity, disfunction of MHCs, irreversible T cell exhaustion, primary resistance to IFN-γ signaling, and immunosuppressive microenvironment. Some oncogenic signaling pathways also contribute to the primary resistance. Under the pressure applied by anti-PD1/PDL1 therapy, tumors experience immunoediting and preserve beneficial mutations, upregulate the compensatory inhibitory signaling and induce re-exhaustion of T cells, all of which may attenuate the durability of the therapy. Here we explore the underlying mechanisms in detail, review biomarkers that help identifying responders among patients and discuss the strategies that may relieve the anti-PD1/PDL1 resistance.

Re-Clustering and Profiling of Digestive System Tumors According to Microenvironment Components

“…Among the different forms of immunotherapy, immune checkpoint blockade (ICB) has achieved significant effects in inhibiting the malignant progression of tumors, including digestive system tumors. But, results from clinical trials show that only a selection of tumor patients respond well to ICB ( 20 ). The difference and complexity of microenvironmental components may partially explain the heterogeneity of the ICB response among tumor patients ( 18 ).…”

Re-clustering and profiling of digestive system tumors according to microenvironment components

“…Immunotherapy has become the most promising option. However, some clinical trials of immune checkpoints blocking (ICB) have shown that only some cancer patients can bene t from it [20]. Therefore, screening and pro ling the subgroups of patients with different responsiveness to ICB treatment will have signi cant clinical value.…”

“…Within these years, more and more studies have begun to focus on immunotherapy, which was considered as a promising therapy in the near future, extensive basic and preclinical research have been carried out. Among them, the most valuable and potential immune regulatory point blocking therapy (ICB) has achieved signi cant effects in inhibiting the malignant progression of tumors including digestive system tumors, while clinical trial results show that there is only a part of tumor patients response well to ICB therapy [20]. The difference and complexity of microenvironmental components may partially explain the heterogeneity of ICB immunotherapy response among one kind of tumor patients [18].…”

TRAIL Promotes Epithelial-to-mesenchymal Transition by Inducing PD-L1 Expression in Esophageal Squamous Cell Carcinomas

“…Next, we investigated the mechanism of TRAIL-induced EMT. Programmed death-ligand 1 (PD-L1), as an immunosuppressive molecule, is highly expressed on the surface of a variety of cancer cells [23]. Recently, it was reported that PD-L1 promotes EMT, and thus induces tumor progression in lung and breast cancer [24][25][26].…”