Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...

/pdf/safety-and-activity-of-anti-pd-l1-antibody-in-patients-with-2g1sbl9vc4.pdf

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.

PD-1 and its ligands in tolerance and immunity

https://www.cell.com/cancer-cell/pdf/S1535-6108(15)00089-6.pdf

Immune checkpoint blockade: a common denominator approach to cancer therapy

▪ Abstract The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also regulate self-tolerance by supporting CD4+CD25+ T regulatory cell homeostasis. CTLA-4 can exert its inhibitory effects in both B7-1/B7-2 dependent and independent fashions. B7-1 and B7-2 can signal bidirectionally by engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells. The five new B7 family members, ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional antigen-presenting cells as well as on cells within nonlymphoid organs, providing new means for regulating T cell activation and tolerance in peripheral tissues. The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and...

The b7 family revisited

Dendritic cells (DCs), unique antigen-presenting cells (APCs) with potent T cell stimulatory capacity, direct the activation and differentiation of T cells by providing costimulatory signals. As such, they are critical regulators of both natural and vaccine-induced immune responses. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified among a library of genes differentially expressed between DCs and activated macrophages. B7-DC fails to bind the B7.1/2 receptors CD28 and cytotoxic T lymphocyte–associated antigen (CTLA)-4, but does bind PD-1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than B7.1 and induces a distinct pattern of lymphokine secretion. In particular, B7-DC strongly costimulates interferon γ but not interleukin (IL)-4 or IL-10 production from isolated naive T cells. These properties of B7-DC may account for some of the unique activity of DCs, such as their ability to initiate potent T helper cell type 1 responses.

/pdf/b7-dc-a-new-dendritic-cell-molecule-with-potent-4mz5d7ld48.pdf

B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells

Introduction Endoscopy training has been significantly impacted by the COVID-19 pandemic. The Joint Advisory Group on GI Endoscopy issued guidance for the recovery of endoscopy training. This provided us with an opportunity to improve endoscopy training with a peer-led programme. Methods The programme involved a group of trainees using the EndoVault® endoscopy system to scrutinise endoscopy lists to establish their suitability for training. A senior trainee was tasked to allocate the endoscopy lists based on trainee availability and current training objectives. The allocations were made on a 2-weekly cycle. We analysed the number of procedures over a 4-month period (1st March-30th June) for 2019, 2020 and 2021. Trainee satisfaction for 2021 was assessed pre- and post-intervention using a Likert scale based survey. Results There was a significant increase in the number of training procedures performed by trainees, comparing 2019 (pre-pandemic) and 2021 (post-intervention) - 21.7% vs. 59.8%, p<0.0001. The greatest increase was access to training in colonoscopy (297%), with also increased access for gastroscopy (270%) and flexible sigmoidoscopy (242%), represented as the change in the proportion of available training procedures performed by trainees comparing 2019 to 2021. Furthermore, trainees performed more independent procedures. Table 1 summarises the number of endoscopic procedures identified and performed by trainees during 2019, 2020 and 2021 (with∗Denotes p<0.001 relative to 2019 data and +denotes p<0.001 relative to 2020 data for comparator proportions represented). The survey showed an improvement in satisfaction of trainees' access to endoscopy with 100% of all responding trainees (n=16) being satisfied (25% pre-intervention). 87.5% of all trainees advised the programme helped them to meet their endoscopy training objectives. Conclusions This programme, devised by trainees for trainees, had a significant improvement in access to endoscopy training. This was further reflected in the results of the satisfaction survey. This programme could easily be applied at other hospital trusts as a model of training delivery.

Ahmed Shalabi

Papers

B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells

P116 A peer-led programme to improve access to endoscopy training

Collective Solipsism in Alfred Tennyson’s “The Lotos-Eaters”

The Analogy between Christopher Marlowe’s Doctor Faustus and the Qur’anic Pharaoh