B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders

Abstract

IntroductionTumorigenesis is associated with a wide array of both genetic and epigenetic changes that give rise to tumor-associated antigens capable of eliciting a host antitumor immune response. Although host immune surveillance may prevent tumor outgrowth during the earliest stages of tumor growth, locally invasive or metastatic tumors must evade host immunity. 1 Immune escape is not merely a passive process of immune evasion but an active one by which both tumor cells and stromal cells present within the tumor microenvironment actively suppress the antitumor immune response. This distinction between immune evasion and suppression is an important one and may explain the paradoxical observation that many tumor immunotherapy clinical trials, despite eliciting an antitumor immune response, are not associated with a meaningful clinical response. 2 Improved mechanistic understanding of tumor-associated immune suppression is needed if the next generation of immunotherapeutic strategies is to be rationally designed.Malignant cells may suppress host immunity directly, by producing immunoregulatory cytokines or expressing inhibitory ligands on their cell surface. In addition, malignant cells may influence the tumor microenvironment leading to the induction or recruitment of immunoregulatory cells capable of suppressing host immunity. 3 Both myeloid-derived cells (including tumor-associated macrophages, dendritic cells [DCs], and myeloid-derived suppressor cells) and lymphocyte subsets, most notably regulatory T (Treg) cells, present within the tumor microenvironment, collaborate with their malignant counterparts to suppress host immunity. 3,4 The microenvironment's role in promoting tumor growth in nonHodgkin lymphoma (NHL) was recently highlighted by both gene expression profiling and immunohistochemistry-based approaches. [5][6][7] Therapeutic approaches capable of targeting the tumor microenvironment are currently being translated into clinical practice in hematologic malignancies and may be associated with improved outcomes. 8,9 Fundamentally, 2 distinct approaches capable of targeting the tumor microenvironment may be imagined. The first seeks to eliminate immunosuppressive cells present within the tumor microenvironment and is highlighted by recent attempts to eliminate Treg. As different stromal cells may use common immunosuppressive mediators, the alternative approach seeks to identify and neutralize these shared molecular mediators of host immune suppression.Members of the B7 family have emerged as important mediators of host immune suppression. In contrast to B7-1 (CD80) and B7-2 (CD86), which play an important role in T-cell activation and costimulation, the B7 homologs (B7-H, including B7-H1, B7-H2, B7-H3, and B7-H4), which have been described more recently may function as important "coinhibitors" of host T-cell immunity and have been associated with poor clinical outcomes in a variety of human tumors. 10,11 B7-H1, for example, may be inducibly expressed on tumor cells and confer resistance to killing media...

The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-B-cell lymphoma

“…First, monocytes and monocytic myeloid-derived suppressor cells suppress host antitumor immunity by a variety of different mechanisms. 47,48 For example, we have previously shown that both peripheral blood monocytes and their progeny within the tumor microenvironment inducibly express the T-cell co-inhibitory ligand B7-H1 (PD-L1). 47 B7-H1 expression was found to directly impair the expansion and effector functions of tumor-specific T cells, and when expressed by myeloid-lineage cells within the tumor microenvironment led to the expansion of suppressive regulatory T cells.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…Lymphoma-derived IL-10, upregulated in patients with advanced-stage disease poorly responsive to therapy [47], impairs the maturation of lymphoma-associated dendritic cells, rendering them immunologically incompetent, thus promoting escape from host antitumor immune surveillance. In addition, lymphoma-associated dendritic cells were observed to express the T-cell coinhibitory ligand B7-H1 (PD-L1, CD274), which directly inhibits the proliferation of tumor-specific T cells, but also indirectly impairs antitumor immunity by promoting the induction of suppressive regulatory T cells [48]. Therefore, lymphoma-associated macrophages and dendritic cells appear to play an important role in cutaneous T-cell lymphomagenesis while contributing to the evasion and suppression of host antitumor immunity.…”

Programmed death 1 is expressed in cutaneous infiltrates of mycosis fungoides and Sézary syndrome

“…Recent work has demonstrated that reverse signaling by B7-H1, after PD-1 engagement, may prevent the induction of apoptosis in tumor cells; thus, cross-talk between B7-H1-and PD-1-expressing malignant T cells may confer resistance to apoptotic stimuli via B7-H1 reverse signaling [13,14]. Further studies to assess the expression and function of PD-1 and B7-H1 in CTCL may be warranted; blocking antibodies for B7-H1 and PD-1 are currently being tested in the clinical trial setting [15].…”