bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reconstitution of peripheral CD4+FOXP3+ regulatory T cells in cancer patients receiving adoptive immunotherapy is related to the clinical response to therapy. (131.18)
Authors: Yao Xin , Ahmadzadeh Mojgan , Rosenberg Steven , Robbins Paul 
Published: January 2023

Abstract
The reconstitution of CD4+FOXP3+ T regulatory cells (Tregs) was evaluated in clinical cancer trials that involved the adoptive transfer of in vitro cultured autologous tumor infiltrating lymphocytes (TIL) in conjunction with IL-2. Reconstituting Tregs present in peripheral blood following adoptive transfer were phenotypically and functionally similar to conventional Tregs. Treatment of patients with non-myeloablative (NMA) chemotherapy in conjunction with total body irradiation (TBI) (n=46) prior to adoptive transfer lead to significantly lower levels of circulating Treg cells one to two weeks after cell transfer compared to patients who received NMA alone (n=24), both when evaluated as the percentage of T cells (median 0.98% vs 6.3%, P&lt;.0001) as well as the absolute cell count (2.3/µL vs 45/µL, P&lt;.0001). The intensity of TBI negatively correlated with Treg reconstitution. The frequency and absolute numbers of circulating Tregs one to two weeks post therapy was directly correlated to the number of administered IL-2 doses in the patients receiving NMA alone, but not in the patients receiving NMA plus TBI. Finally, the ratio of Treg cells to total CD3+ T cells was significantly lower in the clinical responders than in non-responders in both NMA (2.4% vs 16%, P&lt;.01) and NMA plus TBI (0.56% vs 4.6%, P&lt;.0001) groups. These findings suggest that strategies that limit Treg reconstitution may enhance clinical responses in cancer patients receiving adoptive immunotherapy.
Provision of CD4+ T cell help preferentially enhances anti-tumor immunity of high avidity T cells (131.19)
Authors: Zhu Ziqiang , Singh Vinod , Bronte Vincenzo , Feigenbaum Lionel , Hurwitz Arthur 
Published: January 2023

Abstract
It has been shown that high avidity tumor-specific CD8+ T cells are superior to low-avidity T cells in anti-tumor activity. However, adoptive transfer of high-avidity CTL populations could still fail as a therapy due to the fact that CTL effector function may be lost following tumor infiltration. To investigate whether provision of CD4+ T cell help will enhance the effectiveness of high avidity CTLs in anti-tumor immunity, we utilized transgenic mice developed in our lab which bear different TCR transgenes specific for a common melanoma differentiation antigen, tyrosinase-related protein 2 (TRP-2(180-188)). T cells from clone 24 Tg mice (TCRhi) show higher avidity than those from clone 37 Tg mice (TCRlo) based on tetramer dissociation and in vitro effector function assays. Here we report that co-activation of CD4+ T cells with TCRhi cells can boost the in vitro function of TCRhi cells, including proliferation, IFN-gamma secretion, Gr-B secretion, and antigen-specific cytotoxicity, but had minimal effects on TCRlo cells. In the treatment of subcutaneous B16 melanoma, we observed that adoptive co-transfer of CD4+ T cells with TCRhi cells (not with TCRlo cells) markedly suppressed tumor growth and induced autoimmune depigmentation at the sites of vaccination and tumor challenge. These findings suggest that provision of CD4+ T cell help preferentially enhances anti-tumor immunity of high-avidity T cells, which may have critical implications for cancer therapy.
Antigen nonspecific memory CD8 T cells expand and gain effector function in response to immunotherapy or to viral infection (131.28)
Authors: Wilkins Danice , Tietze Julia , Alderson Kory , Weiss Jon , Bouchlaka Myriam , Priest Stephen , Taub Dennis , Wiltrout Robert , Longo Dan , Baumgarth Nicole , Blazar Bruce , Redelman Doug , Murphy William 
Published: January 2023

Abstract
Memory CD8 T cells (CD44hi+) have a wide distribution in peripheral blood, secondary lymphoid and non-lymphoid tissues and are hallmarked by their ability to respond rapidly to antigenic re-challenge. We observed that systemic cytokine immunotherapy (IT) results in the marked expansion of memory CD8 T cells due to the preferential expansion of pre-existing memory T cells and not the conversion of naïve (CD44lo+) T cells to an activated phenotype. These CD8 T cells express NKG2D and have cytolytic activity; however, a lack of increased CD25 and PD-1 expression suggests that the expansion and activation are independent of TCR engagement. Studies of CD8 T cells from OT-1 TCR transgenic mice after IT demonstrated the increased lysis of ova-negative tumor targets; moreover, the OT-1 CD8 T cells possessed a memory phenotype and lacked CD25 expression in the absence of ova vaccination. To determine if memory CD8 T cells play a role in pathogenic situations, mice were infected with influenza and tissues were examined for the presence of CD25-NKG2D+ memory CD8 T cells. Interestingly, these cells expanded rapidly in the lungs of infected mice but not peripheral tissues, indicating that memory T cells may play a role in the clearance of pathogen, regardless of antigen specificity. These data suggest that resident tissue memory CD8 T cells may act in reserve as innate effectors and thus bridge the gap between adaptive and innate immunity in cancer immunotherapy and viral infections.
Combinatorial TNF-related Apoptosis-inducing Ligand (TRAIL) plus CpG immunotherapy shows efficacy against metastatic renal cell carcinoma in mice (131.32)
Authors: Norian Lyse , Kresowik Timothy , Kucaba Tamara , Lightfoot Andrew , Rosevear Henry , Schwarz Christopher , Griffith Thomas 
Published: January 2023

Abstract
Metastatic renal cell carcinoma (RCC) is a uniformly fatal disease for which new therapies are urgently needed. Current immunotherapies for RCC have shown some clinical efficacy, but the average survival time for patients remains 6 months. We developed a murine model of metastatic RCC, in which tumor cells transplanted into the kidney spontaneously metastasize to the lungs, then used this model to determine whether immunotherapy administered at the primary tumor site could diminish metastatic tumor outgrowth. Therapy consisted of adenovirus-encoded TRAIL given in combination with CpG 1826. To facilitate quantitation of metastatic tumor spread, we generated a Renca-Luciferase tumor cell line, and analyzed tumor burdens over time via bioluminescent imaging. We found that intra-renal injection of AdTRAIL+ CpG led to a massive influx of dendritic cells and T cells, resulting in diminished primary tumor outgrowth, decreased numbers of lung metastases, and decreased total body tumor burdens. Tumor clearance was dependent upon CD8+ T cells, and required the use of both AdTRAIL and CpG 1826. Thus, a combinatorial immunotherapy that simultaneously increases tumor cell apoptosis via TRAIL, and augments T cell-based antitumor immunity via CpG, when given locally at the site of primary tumor growth, can initiate protective, systemic antitumor immunity against metastatic RCC. Further optimization of such an approach could prove efficacious for patients with inoperable metastatic RCC.
Boosting anti-tumor immunity by combining gp96-Ig vaccination and Ig-mTL1A fusion protein (131.33)
Authors: Khan Samia , Deyev Vadim , Podack Eckhard 
Published: January 2023

Abstract
We previously developed a cell-based vaccine system that secretes heat shock protein gp96 as an Ig fusion protein that efficiently enhances the cross presentation of tumor antigens to CD8+ cytotoxic T lymphocyte (CTL), leading to a tumor antigen-specific clonal expansion. Regulatory T cells (Tregs) in the priming site impose a brake that restricts the full potential of this CTL expansion. In independent studies of TNFR25 and its ligand, TL1A, we found that TNFR25 signaling inhibits the suppressive activity of Tregs and blocks their de novo biogenesis. Combination immunotherapy studies using hamster anti-mouse TNFR25 agonist antibody, 4C12, and vaccine show enhanced tumor rejection in comparison to vaccine only. We have genetically engineered Ig-mTL1A fusion proteins that differ in retention of the cleavage site in the extracellular domain fused to the C-terminus of the mIgG Fc fragment. These fusion proteins are expected to show similar tumor rejection when used in combination therapy with vaccine and, unlike 4C12, are not expected to elicit an antibody response due to prolonged use. The in vitro potencies of the secreted fusion proteins were confirmed by cytotoxicity and binding assays and protein molecular weights were determined by fast protein liquid chromatography (FPLC). We will optimize purification methods to produce the most functional Fc-mTL1A resulting in the strongest TNFR25 signaling, which can be utilized in combination with vaccine for therapeutic benefit.
Polyelectrolyte microcapsules: antigen delivery vehicles for potent induction of CTL responses (131.34)
Authors: Grooten Johan , De Geest Bruno , Naessens Thomas , De Smedt Stefaan , De Koker Stefaan 
Published: January 2023

Abstract
Developing effective cancer vaccines is thought to require the strong activation of cytotoxic T cells (CTLs) to kill transformed cells. Initiation of such CTL responses requires DCs presenting the antigen via the MHCI route, a feature hardly achievable using soluble antigens. Internalization of particulate antigens in contrast has been shown to strongly promote MHCI mediated antigen presentation. In this study, ovalbumin (OVA) was encapsulated in polyelectrolyte microcapsules (PEM), a new class of particles allowing efficient antigen encapsulation under non-denaturing conditions. OVA-loaded PEM strongly promoted MHCI mediated OVA presentation by DCs in vitro and in vivo. Being attractive tools to enhance antigen presentation, PEM however fail to activate DCs, a prerequisite for the initiation of potent CTL responses. To cope with this issue, we coated the surface of cationic PEM with oligonucleotides containing unmethylated CpG motifs, which are strong activators of DCs by triggering TLR9. Co-delivery of CpG and OVA-loaded microcapsules synergistically increased the strength of the CTL response, indicated by a dramatic increase in the number of IFN-γ secreting CTLs and a strongly enhanced killing of OVA peptide-pulsed splenocytes after adoptive transfer. Finally, immunisation with CpG-modified capsules was able to confer protective immunity against a lethal challenge with the highly aggressive OVA-transduced B16 melanoma, clearly demonstrating the potential of this approach.
Interleukin-2 significantly upregulates CD86 expression on T cells during cytokine therapy (131.35)
Authors: Paine Ananta , Kirchner Hartmut , Oelke Mathias , Blasczyk Rainer , Eiz-Vesper Britta 
Published: January 2023

Abstract
Interleukin-2 (IL-2) is one of the most widely used cytokines in therapeutic applications, and its efficacy in the treatment of various cancers and chronic viral infections has been extensively tested. Several studies have focused on the impact of IL-2 on T-cell survival and proliferation. However, very few have focused on IL-2-induced phenotypic changes in T cells, although this is particularly relevant to cytokine therapy. To gain insight into this issue, we analyzed blood samples from patients receiving IL-2 therapy in order to elucidate the phenotype changes occurring in their T cells. A key finding was a marked increase in CD86 expression on CD4+ and CD8+ T cells. Detailed characterizations of the corresponding cytokine-induced CD86 expression profiles on T cells were obtained in subsequent in vitro experiments. We found that the IL-2-induced CD86 molecules are unable to provide costimulatory signals to antigen-specific T cells during activation. Moreover while these CD86 molecules shown to have no binding affinity for CD28 molecules, their binding affinity for the inhibitory molecule CTLA-4 remained intact. Therefore, it is likely that the IL-2-induced CD86 expression on T cells have a modulatory role on IL-2-induced inflammatory response and its related side effects.
Selective targeting of tumor vasculature by cytotoxic T lymphocytes specific for tumor endothelial marker-8 (131.36)
Authors: Perambakam Supriya , Ro Esther , Peace David 
Published: January 2023

Abstract
Tumor endothelial marker 8 (TEM8) is uniquely expressed on tumor vasculature but is absent on normal adult vasculature or somatic tissues, making it an attractive target for immunotherapy. The aim of the current study was to induce human cytotoxic T lymphocytes (CTL) with specificity for TEM8 with the end objective of starving tumors by sustained immunological disruption of their vascular supply. Two HLA-A0201 binding peptide epitopes, TEM8207-215 and TEM8298-306 were identified based on predictive algorithms in silico and T2 binding assays in vitro. Individual CTL cultures were established by stimulation of peripheral blood mononuclear cells with peptides in HLA-A2+ healthy donors. CTL induced with each of these peptides mediated lysis of T2 cells pulsed with the respective TEM8 peptide, but not control HIV-RT476-484 peptide, in chromium release assays. However, only CTL induced with TEM8298-306 peptide exhibited specific lysis of an HLA-A2+ TEM8+ HepG2 tumor cells, indicating that TEM8298-306 is a naturally processed peptide epitope. Further characterization of this CTL demonstrated specific secretion of INF-γ and TNF-α per multiplex cytokine arrays. TEM8298-306 peptide does not share sequence homology with peptides derived from other members of the vWF type-A domain family, notably capillary morphogenesis protein-2 which is widely expressed on normal tissues. These results suggest that TEM8298-306 peptide can be safely used in vaccine formulations for tumor immunotherapy.
CpG-conjugated apoptotic tumor cells elicit potent tumor immunity (131.41)
Authors: Shirota Hidekazu , Klinman Dennis 
Published: January 2023

Abstract
Cancer immunotherapy seeks to induce protective immune responses to tumor-associated antigens (TAA), thereby mediating the eradication of tumor cells. While whole tumor cells represent a comprehensive source of TAA (eliminating the need to identify individual Ags on tumors from different individuals), they tend to be poorly immunogenic. To address this concern, we covalently conjugated immunostimulatory CpG oligodeoxynucleotides (ODN) onto apoptotic tumor cells and examined their ability to induce TAA-specific immune responses. Results show that CpG-conjugated tumor cell vaccines are highly immunogenic. CpG-conjugation enhances the uptake of target cell by DC, triggers the up-regulation of co-stimulatory molecules, and promotes the production of immunomodulatory cytokines (such as IL-12). Vaccination with CpG-conjugated tumor cells stimulates the expansion of tumor-specific CTL that reduce the growth of established tumors. These results suggest that the adjuvant properties of CpG ODN can be harnessed to improve cancer immunotherapy.
T cells with a specific motif in the CDR3-beta region protect mice from CT26 tumor growth (131.46)
Authors: Slansky Jill , Kappler John , Moore Brandon , Dege Carissa , Pennock Nathan , Sprague Jonathan , Franks Alexis , Jordan Kimberly 
Published: January 2023

Abstract
Vaccination with peptide mimics of tumor antigens, or mimotopes, is a potential strategy for antigen-specific immunotherapy of cancer. To determine how to elicit the most effective antigen-specific cytotoxic response against tumors, we have assembled a set of mimotopes of AH1, the immunodominant antigen from the mouse CT26 tumor. Although the AH1 antigen is an ineffective immunogen, vaccination with some of the mimotopes is very successful in protecting mice from tumor growth. The majority of AH1-specific T cells responding to the vaccine or tumor express V-beta 8 gene segments. However, tumor protection by the mimotope vaccines correlates with stimulation of T cells with a more restricted TCR V-beta repertoire. These T cells express receptors that encode a relatively short CDR3-beta motif. This motif consists of a small amino acid, a non-hydrophobic amino acid, a germline-encoded tyrosine, and the J-beta 2.6 gene segment. These results suggest that protective mimotopes enhance antitumor immunity, in part, by increasing the expansion of a subset of functional tumor-specific T cells that naturally respond to the tumor, not a new repertoire of T cells only elicited by the mimotope. We will test the hypothesis that specific T cells with this motif impart increased protection because they have higher affinity for the antigen complex than specific T cells without the motif.
Chicken HSP70 DNA xenogeneic vaccine inhibits tumor growth in a canine cancer model (131.8)
Authors: Yu Wen-Ying , Chuang Tien-Fu , Fischer Laurent , Chu Rea-Min 
Published: January 2023

Abstract
Immunization with xenogeneic DNA is a promising cancer treatment, as it generates immune responses to break tumor tolerance to self-antigens. Heat shock protein 70 (HSP70) is overexpressed in many kinds of tumors and is believed to be heavily involved in tumor progression. This study used a chicken HSP70 (chHSP70) xenogeneic DNA vaccine to elicit immune responses in a beagle canine transmissible venereal tumor (CTVT) model. Two vaccination groups were created: the first (G1) was designed to evaluate the prophylactic efficiency of the chHSP70 DNA vaccine by delivering the vaccine prior to tumor inoculation; the second (G2) was designed to evaluate the treatment efficacy by vaccinating the dogs after tumor inoculation. CTVT dogs received empty vector vaccination and no treatment (CW) were used as controls. Tumor growth was notably inhibited only in the G1 dogs, in which tumors were regressed much earlier than in G2 and CW dogs. The CD4+ subset in tumor infiltrating lymphocytes from G1 dogs was significantly increased than in G2 and CW dogs. The tumor-specific cytotoxicity of PBMC from both G1 and G2 dogs was dramatically enhanced, and ELISpot assay indicated that the canine HSP70 IFN-γ secreting lymphocytes were much more abundant in G1 than in G2 during tumor regression. It was concluded that xenogeneic chHSP70 DNA vaccine successively breaks the tumor tolerance against canine HSP70 and exhibits promising prophylactic activity to inhibit the growth of HSP70-expressing tumor.
An innovative strategy to enhance cross-presentation in dendritic cell-based vaccines (131.9)
Authors: Zhang Tong , Hung Chien-Fu , Wu Tc 
Published: January 2023

Abstract
Immunotherapy has emerged as an important approach for combating cancer. Dendritic cell (DC)-based vaccines are a promising form of immunotherapy because of their ability to induce tumor antigen-specific T cells. Although there are many methods for preparing DC-based vaccines using full-length proteins, cell-penetrating peptides (CPP) have shown success in their ability to deliver whole proteins into DCs and induce antitumor immunity via cross-presentation to CD8+ T cells. This process, however, is limited by the necessity to covalently link the protein of interest to CPP. In our study, we use LAH4, a histidine-rich amphipathic CPP previously used as a DNA transfection reagent, as a novel method of protein delivery that does not require covalent linkage. Our results show that LAH4 mixed with protein could form complexes detectable by immunofluorescence and flow cytometry. We have also shown that LAH4 were capable of complexing with a variety of proteins to bind with different cell types. Furthermore, our data indicate that LAH4 cell binding is partially mediated through surface heparan sulfates. More importantly, DCs incubated with LAH4 mixed with a model antigen, chicken ovalbumin (OVA) protein, were able to significantly activate OVA-specific OT1 T cells compared to OVA protein alone. Thus, we have demonstrated that LAH4 is able to transduce whole protein into cells and has potential to be used as a novel strategy in improving DC cross-presentation in tumor immunotherapy.
Expression and regulation of Toso, a new Fc receptor for IgM, during B cell development (132.15)
Authors: Choi Seung-Chul , Narayanan Sriram , Krzewski Konrad , Borrego Francisco , Coligan John 
Published: January 2023

Abstract
Fc receptors (FcRs) are key regulators of the immune response. A receptor specific for IgM (FcμR) has been recently identified and shown to be predominately expressed on human B cells. FcμR, known previously as TOSO and as Fas apoptosis inhibitory molecule 3 (Faim3), has no role in the inhibition of Fas-mediated apoptosis. We have examined the expression of FcμR in mouse splenocytes by real-time PCR. We found significantly higher levels of FcμR mRNA expression on B cells compared with FcμR mRNA expression on T cells, NK cells, granulocytes, macrophages and monocytes. After stimulation with LPS, anti-CD40 or anti-IgM, FcμR mRNA expression was dramatically down-regulated on splenic B cells. We have also found that bone marrow B cells have lower levels of FcμR mRNA expression than splenic B cells. Furthermore, we analyzed FcμR mRNA expression during B cell development in the bone marrow and we found that immature and mature B cells express high levels of FcμR mRNA compared with pro- and pre- B cells. Currently, we are investigating the role that FcμR plays in B cell development and signaling.
Agonist CD40 antibody mediated stimulation of antigen presenting cells cannot replace CD4+ T help for an effective CD8+ killer response (132.20)
Authors: Ahmed Khawaja , Xiang Jim 
Published: January 2023

Abstract
CD8+ cytotoxic T lymphocytes (CTL) play a central role in the defense against a range of viral, bacterial and parasitic infections. However, the mechanisms by which CD4+ T-cells provide help remain largely elusive. Here, we investigated the concept of replacing CD4+ T-cells requirement for an effective CTL by stimulating antigen presenting cells (APCs) through agonist-CD40 antibody (Ab). C57BL/6 (B6) and MHC class II knockout (KO) mice were intravenously immunized with agonist-CD40 Ab-crosslinked OVA-pulsed DCs (DCova) derived from B6 as well as MHC II KO mice. Consistent with previous work, CD8+ killer response was elicited in MHC class II KO mice, even in the absence of CD4+ T help. Interestingly, DCova from B6 mouse mounted significantly (p&lt;0.05) higher CTL response in B6 mice in comparison to MHC class II KO mice. In contrast, MHC class II KO mouse-derived DCova stimulated lower and roughly similar CTL response both in B6 and MHC class II KO mice. Notably, booster immunization revealed that, although agonist-CD40 Ab endowed DCova (MHC class II KO) the ability to activate CD8+ T killers in the absence of CD4+ T help, but failed to imprint memory programme both in B6 and MHC class II KO mice. Thus, our findings suggest that CD40 ligand (CD40L)-CD40 signaling alone to APCs cannot provide complete help, and besides CD40-CD40L, some other immune components must also be contributing to DC-CD4+ T cell cross-talk for an effective CTL response.
Identification and characterization of highly expressed microRNAs (miRNAs) in memory CD8 T cells (132.21)
Authors: Li Hoi Ming , Weng Nan-ping 
Published: January 2023

Abstract
MicroRNAs are ~22-23 nt single strand RNAs that function in repressing gene expression through inhibiting translation or destabilizing message RNA. Although miRNAs play important roles in lymphocyte development, it is currently unclear if miRNAs regulate differentiation and function of memory T cells. Using a microarray approach, we screened differentially high expressed miRNAs in human memory CD8 T cells and identified five candidate miRNAs that expressed at least two-fold higher in memory than in naïve CD8 T cells. We then analyzed their expression in naïve, central (Tcm) and effector (Tem) memory CD8 T cells by a quantitative RT-PCR method. Only two of them (miR-223 and miR-23a) showed a consistent higher expression in Tcm than in naïve CD8 T cells. Currently, we are analyzing their expression kinetics during activation and aging, and screening their potential target genes.