Stromal elements present within the tumor microenvironment may suppress host immunity

Stromal elements present within the tumor microenvironment may suppress host immunity and promote the growth of malignant lymphocytes in B cell-derived non-Hodgkin lymphoma (NHL). the data presented provide the first evidence implicating B7-H1 in the suppression of host immunity in T-cell lymphoproliferative disorders and suggest that the targeting of B7-H1 may represent a novel therapeutic approach. Introduction Tumorigenesis 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 p-Coumaric acid 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 GIII-SPLA2 is needed if the next generation of immunotherapeutic p-Coumaric acid 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 non-Hodgkin lymphoma (NHL) was recently highlighted by both gene expression profiling and immunohistochemistry-based approaches.5-7 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 p-Coumaric acid 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 mediated by cytotoxic T lymphocytes (CTLs) induce apoptosis of tumor-specific T cells and contribute to the induction of T-cell unresponsiveness including T-cell anergy and exhaustion.11 12 In addition B7-H1 expressed by myeloid-derived cells and Treg within the tumor microenvironment may further contribute to the suppression of host immunity. For example B7-H1+ Treg infiltrating B cell-derived NHLs inhibit the proliferation of conventional T cells in a B7-H1-dependent manner.13 In contrast to B cell-derived NHLs which represent the majority of NHLs in Western nations T-cell NHLs are derived from mature (ie postthymic) T cells and are generally with rare exceptions associated with a poor p-Coumaric acid prognosis. Therefore we sought to examine the role of B7-H1 in the suppression of host immunity p-Coumaric acid in T-cell lymphoproliferative disorders. Methods p-Coumaric acid Cell lines proliferation and cytotoxicity assays The.