Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Bridging the Gap: Connecting the Mechanisms of Immune-Related Adverse Events and Autoimmunity Through PD-1

The emergence of anti–cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), anti–programmed cell death 1 ligand (anti–PD-1), and anti–PD-L1 antibodies as immune checkpoint inhibitors (ICIs) revolutionized the treatment of numerous types of tumors. These antibodies, both alone and in combination, provide great clinical efficacy as evidenced by tumor regression and increased overall patients’ survival. However, with this success comes multiple challenges. First, while patients who respond to ICIs have outstanding outcomes, there remains a large proportion of patients who do not respond at all. This all-or-none response has led to looking downstream of programmed cell death 1 (PD-1) for additional therapeutic targets and for new combination therapies. Second, a majority of patients who receive ICIs go on to develop immune-related adverse events (irAEs) characterized by end-organ inflammation with T-cell infiltrates. The hallmarks of these clinically observed irAEs share many similarities with primary autoimmune diseases. The contribution of PD-1 to peripheral tolerance is a major mechanism for protection against expansion of self-reactive T-cell clones and autoimmune disease. In this review, we aim to bridge the gaps between our cellular and molecular knowledge of PD-1 signaling in T cells, ICI-induced irAEs, and autoimmune diseases. We will highlight shared mechanisms and the potential for new therapeutic strategies.

Scar Sarcoidosis as Presenting Finding in Pembrolizumab Induced Systemic Sarcoidosis in Stage III Melanoma: A Case Report

Immune checkpoint blockade using inhibition of Programmed Cell Death-1 (PD-1) improves both progression-free and overall survival in patients with advanced melanoma, but is associated with a unique set of toxicities termed immune-related Adverse Events (irAEs). We present a case of a man with stage IIIc melanoma who was treated with pembrolizumab (anti PD-1). Two months after initiation of the therapy, the patient developed subcutaneous nodules on his upper lip and right knee, both in a pre-existing scar. Histological examination showed non-necrotising granuloma, most consistent with sarcoidosis. PET-CT showed hypermetabolic mediastinal and hilar adenopathies as well as lung lesions and some cutaneous and subcutaneous metabolic hot spots. Bronchoscopy with biopsy of a lymph node confirmed the diagnosis of sarcoidosis. Pembrolizumab was withheld, whereby a gradual decrease and near spontaneous resolution of all lesions was seen over a period of approximately 6 months. The patient is currently in follow up with no evidence of disease recurrence.Our case shows a unique presentation of sarcoidosis in old scar tissue as presenting symptom of pembrolizumab-related systemic sarcoidosis and demonstrates the importance of histological examination of new lesions occurring during checkpoint inhibitor therapy in order to avoid misdiagnosis of melanoma progression.

Advances in targeting programmed cell death 1/programmed cell death-ligand 1 therapy for hematological malignancies

Programmed cell death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are important immune checkpoints, and their interactions can mediate immune suppression in the tumor microenvironment. Targeting PD-1 and PD-L1 are immune checkpoint inhibitors that bind to PD-1 and PD-L1, respectively, to block the signal pathway between the two and increase the immune response. They are widely used in tumor treatment and have good efficacies for malignant melanoma, renal cell carcinoma, and non-small cell lung cancer, among others. In addition, for hematological malignancies, studies targeting PD-1 and PD-L1 have achieved gratifying results. This article briefly reviews the mechanisms of action and clinical and hematological malignancy applications of targeting PD-1 and PD-L1. Keywords: PD-1, PD-L1, mechanism of action, hematological malignancy