Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies

Abstract

Tumor cells evade immune destruction, at least partially, by upregulating inhibitory signals to limit effector T cell activation. Programmed death 1 (PD-1) is one of the most critical co-inhibitory molecules limiting the T-cell antitumor response. PD-1 and its ligands, PD-L1 and PD-L2, are overexpressed by various types of tumors as well as reactive cells in the tumor microenvironment. A growing body of evidence has shown the clinical efficiency and minimal toxicity of PD-1 pathway inhibitors in patients with solid tumors, but the role of these inhibitors in lymphoid malignancies is much less well studied. In this review, we review the pathologic role of the PD-1 pathway in most common lymphoid malignancies and we organize the clinical data from clinical trials of PD-1 pathway inhibitors. Several anti–PD-1 regimens have shown encouraging therapeutic effects in patients with relapsed/refractory Hodgkin lymphoma, follicular lymphoma, and diffuse large B cell lymphoma. Additional progress is needed to foster an improved understanding of the role of anti–PD-1 therapy in reconstituting antitumor immunity in patients with lymphoid malignancies. Upcoming trials will explore the clinical efficiency of combining PD-1 pathway inhibitors and various agents with diverse mechanisms of action and create more therapeutic possibilities for afflicted patients.

Development of bullous pemphigoid during nivolumab therapy

“…In the case of nivolumab-associated BP, altered B-cell function likely plays a role as well. B cells also express PD-1 and PD-1 ligands, 5 and PD-1 inhibition can directly activate B cells in a T-cell–independent fashion 5 . Additionally, immune suppressive B cells, B regulatory cells (B regs ), suppress a variety of autoimmune conditions including the related immunobullous disorder pemphigus vulgaris 6, 7.…”

Oncogenic Signaling Pathways and Pathway-Based Therapeutic Biomarkers in Lymphoid Malignancies

“…58 However, in the cases of tumor, overexpression of PD-Ls in tumor cells and infiltrating cells, owing to genetic alteration, virus infection, or other intrinsic and extrinsic factors, can activate PD-1 signaling and lead to exhaustion of effector T cells after the interaction of PD-1 and PD-Ls. 59,60 Such an immune escaping signaling has been demonstrated to be a major mechanism contributing to oncogenesis, tumor aggression and metastasis. 59 …”

“…59,60 Such an immune escaping signaling has been demonstrated to be a major mechanism contributing to oncogenesis, tumor aggression and metastasis. 59 …”

“…More and more of the checkpoint inhibitors have been approved and translated into clinical immunotherapy management (Tables 1 and 2). 59,61 …”

“…In the microenvironment, as overexpressed PD-L1 engaging to PD-1, effector T-cells are gradually exhausted, leading to immune function impairment and malignant cells escape from immune clearance. 58,59,139 …”