Purpose: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression.Experimental Design: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients.Results: TIGIT expression on CD8 þ T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT þ CD8 þ T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown. Conclusions: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic.

Purpose A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g. ~20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies which increase T cell infiltration to tumors can be efficacious in enhancing immunotherapy response. Experimental Design We performed an unbiased screen to identify FDA-approved oncology agents with ability to enhance T cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms. Results We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T cell chemokines in cancer cells, macrophages and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T cell infiltration, and T cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells. Conclusions These results provide evidence for a novel role of HDACs in modulating T cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacological induction of T cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment.

Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4 ؉ effector memory T cells (T EMs ) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4 ؉ T EMs (unprimed to recipient antigens) mediate GVL against clinically relevant mouse models of chronic phase and blast crisis chronic myelogenous leukemia, without causing GVHD. By creating genedeficient leukemias and using perforindeficient T cells, we demonstrate that direct cytolytic function is essential for T EM -mediated GVL, but that GVL is retained when killing via FasL, TNF-␣, TRAIL, and perforin is individually impaired. However, T EM -mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken IntroductionAllogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative therapy for hematologic malignancies, including acute and chronic leukemias and lymphomas. In an alloSCT, donor T cells in the allograft are critical for reconstituting T-cell immunity in the host 1 and mediate an antitumor effect called graft-versus-leukemia (GVL). [2][3][4][5] Unfortunately, donor T cells also broadly attack recipient tissues, including the skin, bowel, and liver, in a process called graft-versus-host disease (GVHD). GVHD is a major cause of morbidity and mortality in alloSCT, which greatly limits the efficacy and applicability of this life-saving therapy. GVHD is particularly severe when the donor and recipient are not fully major histocompatibility complex (MHC)-matched. This is because the precursor frequency of T cells that recognize non-self-MHC has been estimated to be at least 1000-to 10 000-fold higher than that of T cells that recognize minor histocompatibility antigen peptides presented by self-MHC. Therefore, many centers that perform transplantations using HLA-haploidentical donors rigorously deplete allograft T cells. 6,7 While this T-cell depletion is highly effective in minimizing GVHD, it essentially abrogates donor T cell-mediated immune reconstitution and GVL. Preserving the positive effects of donor T cells-GVL and immune reconstitution-without GVHD remains the central challenge in the alloSCT field.We and others have previously reported that effector memory T cells (T EMs ) do not induce GVHD in MHC-matched and MHC-mismatched models and can transfer functional T-cell memory. [8][9][10][11] This is consistent with the prior demonstration that antipathogen T-cell memory is transferred from donor to recipient in human alloSCT. [12][13][14][15][16] These data suggest a strategy wherein donor T EMs would be selectively infuse...

These data indicate that high level of NETs contributes to lung injury and is correlated with severity of disease. Thus, NETs might be a key factor to predict the poor prognosis in IAV patients.

The behavior and fate of cells in tissues largely rely upon their cross-talk with the tissue microenvironment including neighboring cells, the extracellular matrix (ECM), and soluble cues from the local and systemic environments. Dysregulation of tissue microenvironment can drive various inflammatory diseases and tumors. The ECM is a crucial component of tissue microenvironment. ECM proteins can not only modulate tissue microenvironment but also regulate the behavior of surrounding cells and the homeostasis of tissues. As a nonstructural ECM protein, periostin is generally present at low levels in most adult tissues; however, periostin is often highly expressed at sites of injury or inflammation and in tumors within adult organisms. Current evidence demonstrates that periostin actively contributes to tissue injury, inflammation, fibrosis and tumor progression. Here, we summarize the roles of periostin in inflammatory and tumor microenvironments.