Novel OX40 and 4-1BB derived spacers enhance CD30 CAR activity and safety in CD30 positive lymphoma models.

The chimeric antigen receptor (CAR) derived from the CD30 specific murine antibody, HRS-3, has produced promising clinical efficacy with a favorable safety profile in the treatment of relapsed or refractory CD30-positive lymphomas. However, persistence of the autologous CAR-T cells was brief, and many patients relapsed a year after treatment. The lack of persistence may be attributed to the use of a wild-type immunoglobulin (Ig)G1 spacer that can associate with Fc receptors.

B7-H3-Targeting Chimeric Antigen Receptors Epstein-Barr Virus-specific T Cells Provides a Tumor Agnostic Off-The-Shelf Therapy Against B7-H3-positive Solid Tumors.

Unlabelled: Encouraged by the observations of significant B7-H3 protein overexpression in many human solid tumors compared to healthy tissues, we directed our focus towards targeting B7-H3 using chimeric antigen receptor (CAR) T cells. We utilized a nanobody as the B7-H3-targeting domain in our CAR construct to circumvent the stability issues associated with single-chain variable fragment-based domains. In efforts to expand patient access to CAR T-cell therapy, we engineered our nanobody-based CAR into human Epstein-Barr virus-specific T cells (EBVST), offering a readily available off-the-shelf treatment.

Cord blood-derived V2 and V2 T cells acquire differential cell state compositions upon in vitro expansion.

Human cord blood-derived γδ T cells (CB) display a highly diverse TCR repertoire and have a unique subtype composition different from fetal or adult peripheral blood counterparts. We expanded CB in vitro using an irradiated Epstein-Barr virus-transformed feeder cell-based modified rapid expansion protocol (REP). Single-cell RNA sequencing tracked progressive differentiation of naïve CB into cells expressing neoantigen-reactive tumor-infiltrating lymphocyte as well as tissue-resident memory precursor-like and antigen-presenting cell-like gene signatures.

Determining the Development of Persisters in Extensively Drug-Resistant Acinetobacter baumannii upon Exposure to Polymyxin B-Based Antibiotic Combinations Using Flow Cytometry.

Polymyxin B-based combinations are increasingly prescribed as a last-line option against extensively drug-resistant (XDR) It is unknown if such combinations can result in the development of nondividing persister cells in XDR We investigated persister development upon exposure of XDR to polymyxin B-based antibiotic combinations using flow cytometry. Time-kill studies (TKSs) were conducted in three nonclonal XDR strains with 5 log CFU/ml bacteria against polymyxin B alone and polymyxin B-based two-drug combinations over 24 h. At different time points, samples were obtained and enumerated by viable plating and flow cytometry.

Halted Lymphocyte Egress via Efferent Lymph Contributes to Lymph Node Hypertrophy During Hypercholesterolemia.

Dyslipidemia is a central component of atherosclerosis and metabolic syndrome linked to chronic inflammation and immune dysfunction. Previously, we showed that hypercholesterolemic apolipoprotein E knock out (apoE) mice exhibit systemic effects including skin inflammation and hypertrophic lymph nodes (LNs). However, the mechanisms accounting for LN hypertrophy in these mice remain unknown.

Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site.

Most cancer immunotherapies under present investigation are based on the belief that cytotoxic T cells are the most important anti-tumoral immune cells, whereas intra-tumoral macrophages would rather play a pro-tumoral role. We have challenged this antagonistic point of view and searched for collaborative contributions by tumor-infiltrating T cells and macrophages, reminiscent of those observed in anti-infectious responses. We demonstrate that, in a model of therapeutic vaccination, cooperation between myeloid cells and T cells is indeed required for tumor rejection.

Tumor stroma and chemokines control T-cell migration into melanoma following Temozolomide treatment.

The infiltration of T lymphocytes within tumors is associated with better outcomes in cancer patients, yet current understanding of factors that influence T-lymphocyte infiltration into tumors remains incomplete. In our study, Temozolomide (TMZ), a chemotherapeutic drug used to treat metastatic melanoma, induced T-cell infiltration into transplanted melanoma and into genitourinary (GU) tumors in mice developing spontaneous melanoma. In contrast, TMZ treatment did not increase T-cell infiltration into cutaneous tumors, despite similar increases in the expression of the (C-X-C) chemokines CXCL9 and CXCL10 in all sites after TMZ exposure.

Melanoma-initiating cells exploit M2 macrophage TGFβ and arginase pathway for survival and proliferation.

M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34- but not CD34+ tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34- TICs from chemotherapy in vitro.

Inflammatory lymphangiogenesis: cellular mediators and functional implications.

In adult mammals, lymphatic vessels have been shown to respond to their environment by undergoing lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones. Accumulating experimental and preclinical studies demonstrate that lymphangiogenesis is associated with many inflammatory diseases and may represent an attractive therapeutic target for inflammatory diseases. Thus, a better understanding of how lymphangiogenesis is regulated and contribution to inflammation is critical and may benefit clinical research targeting chronic inflammatory diseases.

The DNA damage response induces antigen presenting cell-like functions in fibroblasts.

The DNA damage response (DDR) alerts the immune system to the danger posed by DNA damage through the induction of damage-associated molecular pattern molecules, chemokines, and ligands for activating immune receptors such as lymphocyte function-associated antigen 1 (LFA-1), NKG2D, and DNAX accessory molecule 1 (DNAM-1). Here we provide evidence that OVA(257-264) -pulsed fibroblasts gain the ability to activate naïve OT-I CD8(+) T cells in response to DNA damage. The ability of fibroblasts to activate OT-I CD8(+) T cells depended on the upregulation of ICAM-1 on fibroblasts and DNAM-1 expression of CD8(+) T cells.

Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D.

Lymphangiogenesis is an important physiological response to inflammatory insult, acting to limit inflammation. Macrophages, dendritic cells, and lymphocytes are known to drive lymphangiogenesis. In this study, we show that neutrophils recruited to sites of inflammation can also coordinate lymphangiogenesis.

CD8 T cells regulate allergic contact dermatitis by modulating CCR2-dependent TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells.

Monocytes and their derived cells have critical roles in inflammation and immune defense. However, their function in skin diseases such as allergic contact dermatitis remains poorly defined. Using a model of contact hypersensitivity (CHS) toward 2,4-dinitrochlorobenzene, we show that Ly6C+ CD11b+ monocytic cells participate in the pathophysiology of CHS and their accumulation is regulated by effector CD8 T cells.

Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL.

Removal of cholesterol from peripheral tissues to the bloodstream via reverse cholesterol transport (RCT) is a process of major biological importance. Here we demonstrate that lymphatic drainage is required for RCT. We have previously shown that hypercholesterolemia in mice is associated with impaired lymphatic drainage and increased lipid accumulation in peripheral tissues.

Hypertonic saline reduces vascular leakage in a mouse model of severe dengue.

Dengue (DEN) is a mosquito-borne viral disease and represents a serious public health threat and an economical burden throughout the tropics. Dengue clinical manifestations range from mild acute febrile illness to severe DEN hemorrhagic fever/DEN shock syndrome (DHF/DSS). Currently, resuscitation with large volumes of isotonic fluid remains the gold standard of care for DEN patients who develop vascular leakage and shock.

Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation.

During inflammation, accumulation of immune cells in activated lymph nodes (LNs), coupled with a transient shutdown in lymphocyte exit, results in dramatic cellular expansion. Counter-regulatory measures to restrain LN expansion must exist and may include re-establishment of lymphocyte egress to steady-state levels. Indeed, we show in a murine model that egress of lymphocytes from LNs was returned to steady-state levels during prolonged inflammation following initial retention.

Impact of postgrafting immunosuppressive regimens on nonrelapse mortality and survival after nonmyeloablative allogeneic hematopoietic stem cell transplant using the fludarabine and low-dose total-body irradiation 200-cGy.

The development of nonmyeloablative (NM) hematopoietic cell transplantation (HCT) has extended the potential curative treatment option of allografting to patients in whom it was previously contraindicated because of advanced age or comorbidity. Acute and chronic graft versus host disease (GVHD) and its consequent nonrelapse mortality (NRM), remains the major limitation of NM HCT. In this report, we analyzed the outcome of 67 patients (median age, 45 years) with hematologic diseases receiving NM conditioning with fludarabine 90 mg/m(2) and total body irradiation (TBI) 200-cGy, followed by filgrastim-mobilized peripheral blood stem cell transplant from HLA identical (n = 61), 5/6 antigen-matched related (n = 1), 6/6 antigen-matched unrelated (n = 3), and 5/6 antigen-matched unrelated (n = 2) donors.

CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women: influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation.

Objective: We examined whether polymorphisms of CYP1A1, which plays a role in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs), confer an increased risk of lung cancer in lifetime non-smoking Chinese women.

Methods: A total of 126 incident lung cancer cases, of which 87.7 were pathologically confirmed, and 162 age-matched hospital controls were included.