Next generation of immune checkpoint therapy in cancer: new developments and challenges

Abstract

Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body’s immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

“…In this study, we also observed that increased transcriptome levels of CD38, HLA‐DRA, IDO1, and LAG‐3 are significantly correlated with BAP1 loss. These immune biomarkers are of extreme importance because they have been associated with different immune‐suppressive pathways, which suggests mechanistic insights for immune suppression and immunotherapy resistance using ICIs . In the protein single‐cell level, we show the functional state of UM infiltrating CD8 + T cells, which co‐express high levels of CD38, HLA‐DR, and CD28.…”

γδ T cells in cancer: a small population of lymphocytes with big implications

“…[121][122][123] The expression of immune checkpoints such as TIGIT, TIM3, LAG3 and NKG2A remains poorly characterised in tumor-infiltrating cd T cells and may provide synergistic targets to combine with conventional T-cell targets such as PD-1. As many cd T cells are not MHCrestricted, the co-inhibitory pathways associated with antigen presentation, such as PD-1 and CTLA-4, may be redundant in their tumor recognition.…”

Stimulating T Cells Against Cancer With Agonist Immunostimulatory Monoclonal Antibodies

“…In addition to CD137, GITR, OX40 and CD27, there are additional costimulatory receptors being targeted for cancer immunotherapy (Cabo, Offringa et al, 2017, Marin-Acevedo, Dholaria et al, 2018). One such receptor is inducible costimulator (ICOS or CD278) which is expressed on activated CD4 + T cells and member of the B7-CD28 family of proteins (Hutloff, Dittrich et al, 1999).…”