bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct interaction with dendritic cells through CD28-CD80/CD86 supports plasma cell survival (34.9)
Authors: Nair Jayakumar R , Carlson Louise M , Rozanski Cheryl , Boise Lawrence H , Chanan-Khan Asher , Lee Kelvin P 
Published: January 2023

Abstract
The long term survival of plasma cells in their bone marrow niches, necessary to maintain persistent antibody titres, depends on specific survival signals that are produced by their interaction with bone marrow stromal cells (BMSC), interactions that remain largely uncharacterized. Both normal and malignant plasma cells (like myeloma cells) express the T-cell co-stimulatory molecule CD28 and are also known to interact with dendritic cells (DC) in bone marrow biopsies. We also know that ligating CD80/CD86 on DCs with soluble CD28/CTLA4 ligands can up-regulate IL-6, an essential plasma cell survival factor. In our studies, co-culturing CD28+ plasma cells (myeloma cell lines or primary plasma cell isolates) with immature DCs significantly up-regulated DC production of IL-6 (400 - 500 pg/ml as opposed to 40 - 70 pg/ml), which was blocked with anti-CD28 antibodies. Cell-free plasma cell-DC co-culture supernatants supported plasma cell proliferation and survival. Furthermore, plasma cell CD28 binding to CD80/CD86 on DCs induces DC expression and activity of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), which inhibits T cell activation by depleting the essential amino acid tryptophan from the microenvironment. Our study suggests a pro-survival role for DC in regulating plasma cell survival by modulating their bone marrow micro-environment
Early Intestinal Epithelial Response to Toxoplasma gondii Infection (39.29)
Authors: Leifer Cynthia A , Ju Chia-hsin , Chockalingam Annapoorani 
Published: January 2023

Abstract
Intestinal epithelial cells are critical for nutrient uptake, but also provide a physical and chemical barrier to infection. When that barrier is breached, epithelial cells can respond and regulate local and systemic immune responses. Toxoplasma gondii (T. gondii) is an orally acquired apicomplexan protozoan intracellular parasite that first encounters intestinal epithelium and then disseminates systemically. Little is known about the responses elicited early during infection in the intestine since studies to date have focused primarily on systemic immune responses through intraperitoneal infection. Furthermore, we lack information on the response of human intestinal cells to live T. gondii infection. Here we examined the early response of human intestinal epithelial cells following infection with T. gondii. Using an in vitro system, we show that human small intestinal epithelial cells infected with T. gondii elicit rapid MAPK phosphorylation, NF-κB nuclear translocation, and secretion of interleukin (IL)-8. Both ERK1/2 activation and IL-8 secretion responses were PI3 kinase-independent yet MyD88- and TLR2-dependent. Although parasite genotype correlates with pathogenicity in mice, all genotypes of T. gondii elicited a similar response through TLR2 and MyD88. Oocysts of T. gondii stimulated cells via TLR2, similar to tachyzoites. Furthermore, we were able to identify many T. gondii-regulated genes in the infected cells using a pathway-focused array. Together, our findings suggest that intestinal epithelial cells recognize and respond to T. gondii during infection, the outcome of which likely modulates intestinal and systemic immunity.
Intramuscular delivery of a plasmid-encoded molecular adjuvant elicits immune responses at mucosal sites in a macaque model (39.51)
Authors: Schoenly Kimberly Ann , Kutzler Michele A , Cisper Neil J , Yan Jian , Khan Amir S , Draghia-Akli Ruxandra , Lewis Mark G , Weiner David B 
Published: January 2023

Abstract
As the primary site of HIV-1 replication is the mucosa, a desirable feature of a HIV-1 vaccine would be the generation of immune responses at mucosal sites. We created an optimized CCL27 DNA construct as well as optimized SIV gag, pol, and env plasmids for immunizing rhesus macaques. Macaques (n=5/group) were immunized with SIV plasmids +/- CCL27. Both immunization groups had significant IFN-g responses against the encoded SIV antigens (~12,000 SFU/106 PBMCs). CD8+ T cell proliferation as measured by CFSE staining was similar between the groups at ~22%. While systemic immune responses were robust, co-delivery of CCL27 did not adjuvant peripheral responses similar to what was observed in mice. Interestingly, macaques that received CCL27 had greater antigen specific IgA at mucosal sites including bronchial lavage and fecal samples. In addition, CD4+ T cells secreting effector cytokines were enhanced in the CCL27 group at mucosal, but not peripheral sites when compared to the antigenic group alone. The CCL27 group also had more polyfunctional CD8+ T cells in the bronchial lavage than the DNA group post-challenge. These data show that a novel chemokine adjuvant may be capable of targeting immune responses to mucosal sites. This strategy may also be applicable to other diseases than HIV-1 where mucosal immune responses are desirable.
Chemokines and recruitment of regulatory T cells to the tumor (40.14)
Authors: Fan Xiaozhou , Allison James P. 
Published: January 2023

Abstract
Foxp3+ regulatory T cells (Treg) are crucial to maintain peripheral tolerance by restraining the reactivity of other immune cells, but this suppressive function is in contrary a great hurdle for successful tumor immunity. Studies in humans have correlated high frequency of Treg to poor prognosis. In a transplantable mouse melanoma model B16/BL6, the tumor is also highly infiltrated with Treg. The aim of this study is to identify the chemokines that specifically recruit Treg to the tumor site and to develop immune intervention strategies to manipulate this traffic. Two C-C motif chemokine receptors, CCR4 and CCR8, have been reported to be expressed preferentially in human Treg. We found that both the two receptors are present on the majority of tumor-infiltrating Treg, with significantly higher frequency than the CD4+ Foxp3- effector T cells (Teff) and the CD8+ compartments. Furthermore, the CCR4+ or CCR8+ Teff are not actively producing IFN-γ, indicating most of the tumor-reactive effector T cells are negative for these receptors. On the other hand, the ligands for CCR4, CCL17 and CCL22, and the one for CCR8, CCL1, are upregulated in the tumors and/or the vaccine sites of the GM-CSF-secreting cellular vaccine (GVAX) as reflected by real-time PCR. These data together suggest that the chemokine-receptor network involving CCR4 and CCR8 could be a potential target for immunotherapy against cancer.
CD73 on tumor cells impairs anti-tumor T cell immunity: a novel mechanism of tumor-induced immune suppression (40.17)
Authors: Zhang Bin , Jin Dachuan , Fan Jie , Liu Aijie , Daniel Benjamin , Shin Tahiro , Curiel Tyler 
Published: January 2023

Abstract
CD73, originally defined as a lymphocyte differentiation antigen, is thought to function as a costimulatory molecule on T lymphocytes and an adhesion molecule that is important for lymphocyte binding to endothelium. We show here that CD73 is widely expressed on many tumor cell lines and upregulated in cancerous tissues. Because CD73 ecto-5'-nucleotidase catalyzes AMP breakdown to immunosuppressive adenosine, we propose that CD73-generated adenosine may prevent tumor destruction by inhibiting antitumor immunity. We confirmed this hypothesis by showing that genetic ablation of CD73 on ID8 ovarian tumor cells by siRNA reduced its enzymatic activity and increased survival and decreased tumor burden in immunocompetent but not immunodificient Rag1-/- mice. CD73 knockdown improved tumor antigen-specific T cell proliferation and CTL in vivo killing function and decreased apoptosis of tumor activated microenvironmental T cells. Notably, there was no therapeutic benefit of adoptive T-cell immunotherapy in mice bearing tumors without CD73 knockdown. By contrast, combining tumor CD73 knockdown and T cell transfer cured all mice. Moreover, blockade of A2A adenosine receptor with its antagonist SCH58261 also augmented the efficacy of T cell therapy. These findings identify a potential mechanism for CD73-mediated tumor immune evasion and point to a novel cancer immunotherapy strategy by targeting tumor CD73.
CD8+ T cell precursor frequency determines the quality of the anti-tumor immune response (40.33)
Authors: Rizzuto Gabrielle A , Merghoub Taha , Hirschhorn-Cymerman Daniel , Liu Cailian , Leskohin Alexander M , Zhong Hong , Panageas Katherine S , Perales Miguel-Angel , Altan-Bonnet Gregoire , Wolchok Jedd D , Houghton Alan N 
Published: January 2023

Abstract
Poor clinical response to cancer vaccines may in part be due to a paucity of self-antigen specific T cells surviving negative selection. Here, we demonstrate the frequency of endogenous, mouse CD8+ T cells recognizing the melanoma/melanocyte antigen gp100 to be &lt;0.0001% (~1 in 1 million). We developed a model to study the responsiveness of different frequencies of CD8+ T cells (pmel-1) against this self antigen. We show that endogenous CD8+ T cell frequency is too low for creating a robust anti-tumor immune response upon vaccination, but supplementing this repertoire with low numbers of naïve pmel-1 cells increases vaccine-elicited tumor immunity. By combining adoptive transfer of only 1000 pmel-1 cells, lymphopenia, and vaccination with mutated self-antigen, we were capable of inducing regression of melanoma tumors in mice.
Curiously, treatment was impaired as the number of tumor-specific cells transferred was increased. At high doses, competition between clones significantly hindered responses. We show that tumor-specific cells primed at low precursor frequencies where competition is not operative, undergo more rounds of proliferation, acquire poly-functionality, and eradicate tumors more effectively. This work demonstrates that precursor frequency can be exploited to augment clinical vaccine strategies. Transfer of optimized numbers of naïve tumor-specific T cells, followed by in vivo activation is a new approach that should be applied to immunotherapy.
IL-21 induced Bcl3 expression blocks type 1 effector differentiation of CD8+ T cells and enhances their tumor efficacy (40.35)
Authors: Shrikant Protul A 
Published: January 2023

Abstract
IL-21 induced Bcl3 expression blocks type 1 effector differentiation of CD8+ T cells and enhances their tumor efficacyCheryl Eppolito, Qingsheng Li and Protul A Shrikant11Department of Immunology, Roswell Park Cancer Institute, 322 Cancer Cell Center, Elm and Carlton Streets, Buffalo, NY. 14263
The γc cytokine; IL-21, induces Jak1/Jak3 mediated STAT1, STAT3 and STAT4 phosphorylation as well as T-bet expression. Surprisingly, IL-21 treated antigen stimulated CD8+ (OT-1) T cells fail to produce IFNγ, although they demonstrate robust cytolytic activity. In addition, IL-21 treatment reduces KGLR1, CXCR3 and CD44 expression while increasing L-selectin, IL-7Ra and CD71 expression, suggesting its ability to dampen effector maturation. The IL-21 induced Jak3 activity is essential for PI3K induced Bcl3 expression. The IKβ member Bcl3 is known to associate with NFkB p50 homodimers and stabilize them for activation and/or repression of specific gene programs that favor anti-inflammatory responses in myeloid cells. The IL-21 induced Bcl3 regulates IFNγ production in OT-1 cells by interfering with STAT1 and STAT4 induced sustained T-bet expression and the loss of Bcl3 renders IL-21 treated OT-1 cells to demonstrate greater effector phenotype. However, the cytolytic maturation induced by IL-21 is only marginally affected by Bcl3 expression. Moreover, IL-21 induced Bcl3 promotes survival of antigen stimulated OT-1 cells and in the absence of Bcl3 the IL-21 conditioned OT-1 cells are less persistent and are ineffective at controlling tumor growth after adoptive transfer. Hence, our results demonstrate a novel pathway by which IL-21 induces "partial" effector maturation, which has greater tumor efficacy. This establishes a new paradigm for the generation of modest effector CD8 T cells that persist for effective ACT mediated tumor therapy.
Supported by NIH-NCI 5R01CA104645 to PAS
Murine mammary carcinoma cells and CD11c+ dendritic cells elicit distinct responses to lipopolysaccharide and exhibit differential expression of genes required for TLR4 signaling (40.4)
Authors: Kurt Robert A , Palha De Sousa Chiquita , Blum Christopher , Sgroe Erica 
Published: January 2023

Abstract
Particular attention has been given to Toll-like receptors (TLR) on dendritic cells (DC) because of their ability to bridge innate and adaptive defenses. Since TLR are also expressed by epithelial cells, and because the majority of cancers are carcinomas, and thus of epithelial origin, we were interested in comparing responsiveness of a carcinoma and DC to a TLR agonist. For this purpose we used the mammary carcinoma 4T1 and CD11c+ DC. Both 4T1 and DC expressed genes encoding multiple TLR and secreted the proinflammatory chemokines CCL2 and CXCL1 in response to the TLR4 agonist lipopolysaccharide (LPS). However, DC, but not 4T1 secreted IL-1beta, TNF-alpha, and upregulated CD80 and CD86 expression following LPS treatment. Gene arrays were used to delineate potential reasons for the differential responsiveness of the cells to LPS. The arrays showed that genes encoding TLR4, CD14, myeloid differentiation primary response gene 88 (Myd88), and Toll-like receptor adaptor molecule 2 (TICAM-2) were expressed at greater levels by the DC; results which were verified by quantitative RT-PCR. These data demonstrate that 4T1 and CD11c+ DC are distinctly responsive to LPS, and that this may be a consequence of differential expression of genes encoding proteins important for TLR signaling.
Ex vivo activity of early cytokine conditioned effector CD8+ T cells inversely correlates with their anti-tumor activity in vivo (41.1)
Authors: Diaz-Montero C. Marcela , Salem Mohamed L. , Naga Osama , Montero Alberto J. , Cole David J. 
Published: January 2023

Abstract
Enhanced effector activity such as cytokine secretion, cell proliferation , cytolytic activity, etc. in response to in vitro stimulation has been widely used as a means to predict in vivo activity after immune mediated interventions, such as adoptive transfer or systemic vaccination. Contrary to this, here we show that the enhanced in vivo survival and anti-tumor activity of cytokine conditioned early activated CD8+ T cells inversely correlates with their effector functions in vitro. When compared with late effector PmelIL-12, early effector showed decreased production of IFNγ and TNFα, and decreased expression of the degranulation marker CD107a in response to in vitro reactivation. However, after transfer into lymphodepleted hosts, early effector PmelIL-12 survived for at least 20 days and were able to effectively control the progression of B16 tumors in a superior manner than late effector PmelIL-12. Thus, effector activity in response to ex vivo antigenic restimulation does not necessarily predict in vivo activity. Other parameters such as surface expression of functional markers (CCR7, CD62L) and /or survival (CD127) could serve as better predictors of in vivo activity. Developing and validating accurate predictors of in vivo lymphocyte function would greatly facilitate our ability to rationally design novel immune based therapies for clinical trials that have significant anti-tumor activity.
Targeting ALDH1A1 for Immunotherapy of Cancer Stem Cells (41.20)
Authors: visus carmen , Wang XinHui , Paola Miyazato , Wang YangYang , Szczepanski Miroslaw , Ferrone Soldano , Deleo Albert 
Published: January 2023

Abstract
Background: ALDH bright cells identify cancer stem cells in breast cancer and other tumors as well. In the past, we were able to generate ALDH1A188-96 peptide specific T cells. Now we hypothesize that ALDH1A188-96 peptide-specific T cells can target cancer stem cells which are otherwise untreatable using available therapies.
Methods: ALDH bright cells were identified by FACS analysis and sorted from head and neck and breast cancer cell lines. Those cells were injected in NOD/SCID mice in order to study their tumorigenicity. The reactivity of the ALDH peptide-specific T cells was tested in IFN-g ELISPOT assays.
Results: ALDH bright cells were isolated from head and neck and breast cancer cell lines and found highly tumorigenic in NOD/SCID mice. ALDH1A188-96 peptide-specific CD8+ T cells recognized ALDH bright cells in ELISPOT assays but did not recognized ALDH negative cells or the bulk tumor cell lines unless those cells were pulsed with the exogenous ALDH1A188-96 peptide.
Conclusion: We are able to target ALDH bright cells for immunotherapy utilizing ALDH1A1 specific T cells and this may result in control of tumor growth and metastasis.
Increased lymphopenia results in higher percentages of FoxP3+ T cells in patients reconstituted by PBMC adoptive transfer and vaccinated (41.36)
Authors: Thompson James  A , Assmann Ilka , Haley Daniel , Moudgil Tarsem L. , Jensen Shawn M. , Poehlein Christian H. , Hu Hong-Ming , Walker Edwin B. , Sacks Natalie , Hege Kristen , Curti Brendan , Urba Walter J. , Fox Bernard A. 
Published: January 2023

Abstract
In clinical trials therapeutic tumor vaccines have failed to provide evidence of efficacy. Based on preclinical tumor models showing that vaccination during homeostasis-driven proliferation improved therapeutic efficacy, we performed a translational phase I/II clinical trial in men with metastatic hormone-refractory adenocarcinoma of the prostate. This strategy has the theoretical advantage that it eliminates regulatory T cells (Treg). Patients were randomized to cohort A, B or C. Cohort A patients (n = 5) received prostate GVAX TM (two prostate cancer cell lines that secrete GM-CSF, Cell Genesys Inc.) vaccination only. Cohort B (n = 5) received cyclophosphamide followed by reinfusion of autologous PBMC and vaccine (GVAX). Cohort C patients (n=5) received same treatment as Cohort B with the addition of fludarabine. We hypothesized that the most lymphopenic patients would have the fewest Treg. While all cohorts showed an increase in the total number and frequency of peripheral Treg, the most lymphopenic patients (cohort C) had the greatest fold increase in peripheral Treg at weeks 2-6 (2.3,1.2,0.7 / p&lt;0.05). Current studies are examining whether adoptive transfer of CD25 depleted PBMC will reduce Treg recovery and improve clinical response.
Supported by CA119123, Robert W. Franz, Chiles foundation, Prostate Cancer Foundation and Providence Medical Foundation
Vaccination with Mimotopes Prevents Tumor Growth by Enhancing the Activation of T cells that Respond to Natural Tumor Antigens (41.40)
Authors: Slansky Jill E. , Jordan Kimberly R. , Kappler John W. 
Published: January 2023

Abstract
Vaccination with mimotopes, or peptide mimics of self-tumor antigens, is a potential strategy for antigen-specific immunotherapy of cancer. We tested mimotopes with substitutions in residues involved in T cell interactions, rather than in conventional MHC-anchor residues, for protection against the transplantable tumor, CT26. Although vaccination with all of the mimotopes elicited tumor-specific T cells more effectively than the wild type tumor antigen, AH1, only some mimotopes prevented tumor growth. Vaccination with the protective mimotopes generated considerably more cross-reactive T cells that produced the cytokine IFNgamma after stimulation with lower concentrations of the AH1 peptide. These T cells expressed TCR molecules with a more restricted Vbeta repertoire ex vivo, but were similar in CDR3 sequence to the T cells generated by vaccination with the AH1 peptide. Importantly, the T cells responding to the non-effective mimotopes did not inhibit the antitumor responses of the protective mimotopes. These results suggest that protective mimotopes generate antitumor immunity, in part, by enhancing the activation and differentiation of a subset of T cells that naturally respond to the tumor, not a new repertoire of T cells only elicited by the mimotope.
Induction of anti-tumor immunity by a protein transfer mediated cancer vaccine (41.49)
Authors: Bozeman Erica Necole , Cimino Ashley M. , Tien Linda , Shashidnamurthy Rangaiah , Selvaraj Periasamy 
Published: January 2023

Abstract
The induction of a robust anti-tumor immune response is essential to the development of an effective cancer vaccine. Our lab has extensively studied a protein transfer approach that would allow for the rapid and stable incorporation of a myriad of immunostimulatory proteins, such as costimulatory molecules and cytokines, to the surface of tumor cell membranes via a glycosylphosphatidylinositol (GPI) -anchor. Using the 4T07 murine breast cancer model, all BALB/C mice immunized subcutaneously with tumor membranes modified to express B7.1, IL-2 and IL-12 alone or in combination were protected against direct and secondary challenges with live tumor cells. Additionally, these modified tumor membranes induced regression of a wild-type tumor growing at a distant site. These results suggest that the addition of immunostimulatory proteins directly to the tumor cells using a GPI-anchor can be proven effective in inducing an anti-tumor immune response that provides protective as well as concomitant immunity in a tumor bearing host.
Gap-junction communication between autologous endothelial and tumor cells induce cross-recognition and elimination by specific CTL (41.58)
Authors: Chouaib Salem , Benlalam Houssem 
Published: January 2023

Abstract
Cellular interactions in the tumor stroma play a major role in cancer progression but can also induce tumor rejection. To explore the role of endothelial cells in these interactions, we used an in vitro 3D collagen matrix model containing a cytotoxic T lymphocyte CTL clone (M4.48), autologous tumor cells (M4T) and an endothelial cell (M4E) line that are all derived from the same tumor. We demonstrate here that specific killing of the endothelial cells by the CTL clone required the autologous tumor cells and involved antigen cross-presentation. The formation of gap-junctions between endothelial and tumor cells is required for antigenic peptide transfer to endothelial cells that are then recognized and eliminated by CTL. Our results indicate that gap-junctions facilitate an effective CTL-mediated destruction of endothelial cells from the tumor microenvironment which may contribute to the control of tumor progression.
T-bet controls CD4+CD25+Foxp-3+ T regulatory cells and Th17 cells in lung adenocarcinoma (41.59)
Authors: Finotto Susetta , Boross Ildiko , Koslowski Michael , Karwot Roman , Maxeiner Joachin , Türeci Olez , Lehr Hans Anton , Finotto Susetta 
Published: January 2023

Abstract
The range of identified effector CD4+ T cell lineages has been expanded to enclose the Th17 cells whose function in lung tumor has not been investigated yet.
In this study, we report increased expression of the two newly identified transcription factors of the Th17 lineage, RORA and RORC2, in the lung of patients affected by lung adenocarcinoma.
Targeting IL-17A in a murine model of lung adenocarcinoma, resulted in local expansion of CD4+ effector T cells producing IFNγ and reduction of CD4+CD25+FOXP3+ regulatory T cells. In support of a protective role of IFNγ in this model, T-bet (-/-) mice exhibited increased tumor load, decreased survival and increased residual CD4+CD25+FOXP3+ T regulatory cells after anti-IL-17A antibodies treatment as compared to wild type littermates.
Thus, blockade of lung Th17 responses requires T-bet to reduce T-regulatory cells for limiting lung cancer.