bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1-expressing B cells promote murine breast cancer development and mediate response to anti-PD-L1 immune checkpoint inhibitor.
Authors: Cervantes Christian , Khan Mustafa Tamim Alam , Liu Zexuan , Viswanadhapalli Suryavathi , Gupta Harshita , Curiel Tyler , Yan Hui , Vadlamudi Ratna , Xu Zhenming 
Published: February 2023

Abstract
B cells promote tumor development in murine models of breast cancer (BCa), – as we have shown – by producing pleiotropic cytokine IL-27, which upregulates expression of PD-L1 immune checkpoint in BCa cells and tumor-infiltrating B cells (TIL-Bs). Paradoxically, B cell activation has been shown to predict a positive response to immune checkpoint inhibitors (ICIs) in murine BCa tumors and melanoma, sarcoma and kidney cancer in humans. Here, we have addressed the role of B cell-expressed PD-L1 in BCa development and responses to ICIs by generating conditional knockout mice in which Cd274 (encoding PD-L1) was ablated only in activated B cells (AicdacreCd274fl/fl). Tumor development in AicdacreCd274fl/fl mice from engrafted syngeneic ER+ E0071 BCa cells was significantly delayed, albeit not abolished (as occurring in mice lacking B cells), with a marked increase in CD86 B-cell expression, a key agonistic ligand for T cell-expressed CD28 (a co-stimulatory receptor whose function is inhibited by the PD-L1/PD-1 immune checkpoint). The heightened B-cell CD86 expression in AicdacreCd274fl/fl mice was recapitulated in vitro using CD154, a T helper cell stimulus critical for B cell activation and differentiation. Treatment with anti-PD-L1 (aPD-L1) boosted wildtype B cells, stimulated with CD154 in vitro, to express CD86 and differentiate into potentiated plasma cells. Thus, PD-L1+ TIL-Bs use PD-L1 to impose a “brake” on host anti-tumor activity but are directly targeted by aPD-L1 to relieve the brake, which “jump-starts” CD86:CD28 signaling and potentiates the anti-tumor response. Thus, providing a mechanistic explanation for the opposing roles of B cells in murine BCa development and ICI responses.
Neoantigen driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses
Authors: Cui Can , Joshi Nikhil S. , Craft Joseph E 
Published: February 2023

Abstract
CD4+ TFH cells provide help to B cells, which is critical for germinal center (GC) formation. Although the presence of these cells is correlated with favorable clinical outcomes in various cancer types, little is known about how TFH and B cells function in anti-tumor immunity. Through the analyses of survival and bulk expression data in The Cancer Genome Atlas (TCGA) and single cell RNA sequencing data, we found that TFH cells correlated with GC B cells and with prolonged survival of lung adenocarcinoma (LUAD) patients. To further investigate if and how TFH-B cell interactions evoke protective anti-tumor responses, we developed the KP-HELLO murine lung adenocarcinoma model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens (HEL, LCMV GP33–43/FLAG/GP61–80, and codon-Optimized mScarlet). KP-HELLO tumors triggered tumor-specific TFH and GC B cell responses, which were necessary for tumor control, as were effector CD8+ T cell responses. The latter were reduced in the absence of T cell-B cell interactions or the IL-21 receptor. IL-21 was produced primarily by TFH cells, development of which required B cells. Moreover, development of tumor-specific TFH cell-responses was also reliant upon tumors that expressed B-cell-recognized neoantigens, which suggested that tumor-neoantigens themselves can control the fate decisions of tumor-specific CD4+ T cells by facilitating interactions with tumor-specific B cells. Our data highlight the importance of B cell-TFH cell collaborations in driving anti-tumor CD8+ T cell responses via IL-21 and indicated that therapeutics targeting B cell-TFH cell-IL-21 axis may be beneficial in patients with lung and other cancers.
Th17 cells enhance CD8 T cell cytotoxicity via IL-21 production in tumor vaccinated mice.
Authors: Lust Hannah E , Huang Yina H 
Published: February 2023

Abstract
A precise tug-of-war between regulatory T (Treg) cells and IL-17-producing (Th17) CD4 T cells ensures appropriate reactivity to pathogenic challenge. While an imbalance favoring Treg activity leads to suboptimal responses, overactive Th17 activity promotes autoimmunity. Both Th17 and Treg cells represent a significant proportion of the tumor infiltrating lymphocytes (TILs) in melanoma patients. In this disease context, Tregs suppress effector cells via numerous mechanisms. Productive immune responses are believed to result from passive escape from Treg suppression. We report an active role for Th17 cells in dampening Tregs to promote CD8 effector T cell activity. Using a melanoma mouse model, we found that elimination of IL-17-producing cells prevents vaccine-induced anti-melanoma immunity. Using RNA-Seq analysis, we identified a gene expression (GE) signature that implicates the IL-21/IL-21R axis in the ability of Th17 cells to inhibit Tregs and to induce a cytolytic GE signature in CD8 T cells. Similarly compromised vaccine-induced anti-melanoma responses in both IL-21R-deficient and Th17 diminished mice further support a critical role for Th17 cells and IL-21. Ectopic expression of IL-21 rescued compromised anti-tumor responses in Th17 diminished mice, suggesting that Th17-specific production of IL-21 induces effective CD8-mediated anti-tumor immunity. Single-cell RNA-seq analysis elucidated dynamic changes in both the identity and phenotype of diverse TILs populations in response to Th17 cells and IL-21 expression. Together, these data suggest that Th17-specific IL-21 production impedes Treg suppression, resulting in increased CD8 T cell effector function, and changes in TILs populations.
Tumor-infiltrating CD8+ T cells can be resident, but exhaustion markers rather than CD69 correlate with residence and tumor specificity
Authors: Gavil Noah Veis , Weyu Eyob , Scott Milcah C. , Smith Olivia , Wijeyesinghe Sathi , Masopust David 
Published: February 2023

Abstract
Tumor infiltrating lymphocytes (TILs) represent a heterogeneous population of both pathogen-specific bystander and tumor-specific CD8+ T cells. Within select solid tumors, the expression of exhaustion markers PD-1 and CD39 has been used to discriminate between pathogen-specific and tumor-specific cells. Independent studies across numerous types of solid tumors have also shown that CD8+ TILs can exhibit distinct signatures that imply residence, however, the migrational properties of TILs have not been fully elucidated. In this study, we employed parabiosis migration assays in a mouse model of breast cancer and demonstrated that both virus-specific bystander and tumor-specific CD8+ T cells within the tumor microenvironment (TME) can be resident. Canonical markers of resident-memory T cells (TRM), including CD69, failed to discriminate between resident cells and recent migrants. However, the expression of markers associated with T cell dysfunction (PD-1, CD39, Tim-3, Lag-3) identified a population of tumor-specific cells and was tightly correlated with residence within the TME. Thus, TRM exist within tumors, durable intratumoral residence was not well informed by common markers associated with TRM in healthy tissues, and the expression of exhaustion markers correlated with both tumor specificity and durable residence.
Dual function of Bim is switched by ANT2 (SLC25A5) to balance apoptotic and effective signals in CD8+ T cells
Authors: Gicobi Joanina K , Yu Xiatong , Dronca Roxana , Zhu Mojun , Dong Haidong 
Published: February 2023

Abstract
The immune responses to anti-PD-1 therapy in cancer patients are not completely defined due to lack of reliable biomarkers that identifies responsive and functional T cells. Bim, a molecule of the Bcl-2 family, was recently identified as a downstream signaling molecule of PD-1 pathway in CD8+ T cells and has both pro-apoptotic and effective roles in CD8 T cells. Our clinical data shown that high level of Bim in CD8+ T cells (before checkpoint blockade) was predictive of response in metastatic melanoma whereas in colorectal cancer, low level of Bim was associated with treatment response. Using co-immunoprecipitation, high resolution microscopy and FRET we identified ANT2 (Adenine Nucleotide Translocase 2, an inner membrane protein of mitochondria) as a protein interacting with Bim. Accordingly, we found CD8+ T cells with low and high mitochondrial potential demonstrated different ANT2/Bim ratio, and high ANT2/Bim ratio fall in effector T cells with low mitochondrial potential but high cytotoxic activity. Given the pro-survival of ANT2, our results indicate that ANT2 may function to balance the pro-apoptotic and effective role of Bim in mitochondria in order to preserve effector T cells before contraction. Understanding the molecular mechanism of Bim and ANT2 interaction in CD8+ T cells may provide a novel marker to identify resilient CD8+ T cells responsive to anti-PD-1 therapy, and predict clinical response to the therapy.
The role of c-Jun in enhancing TCR-T function in treatment of Hepatocellular Carcinoma
Authors: Hussein Mohamed Ahmed Shawky , He Yukai 
Published: February 2023

Abstract
Hepatocellular carcinoma (HCC) is responsible for most of primary liver cancer cases and is the sixth most common cancer in the world with a general 5 year survival rate of 18% due to lack of effective therapy. Adoptive T-cell therapy (ACT) with T-cell receptor–engineered T-cell (TCR-T) against HCC-associated antigen a-fetoprotein (AFP), can redirect human T cells to recognize and kill HCC tumor cells. However, the clinical efficacy of TCR-T therapy is dependent on the proper expansion, in vivo persistence of T cells that is markedly reduced due to exhaustion-associated dysfunction, and activation induced cell death. To improve persistence of TCR-T cells without modifying TCR affinity, we engineered TCR-T cells to overexpress c-Jun, an AP-1 transcription factor associated with T cell development and activation. In this study, we showed that TCR-T cells overexpressing c-Jun have enhanced expansion capacity in culture, improved cytokine production against HepG2 tumor cells without altering their cytotoxic potential. Interestingly TCR-T cells overexpressing c-Jun showed resistance to activation induced cell death with decreased expression of inhibitory receptors after stimulation with HepG2 tumor cells. Thus, c-Jun overexpression could be a potential therapeutic agent to enhance the anti-tumor efficacy of TCR-T cells against HCC.
CD19 loss by CAR T cell mediated trogoctyosis is regulated by CAR affinity
Authors: Olson Michael , Luetkens Tim , Atanackovic Djordje 
Published: February 2023

Abstract
CD19 CAR T cell therapy has entered the spotlight for the treatment of B cell lymphoma, however, relapse with CD19 negative disease is common in many subtypes of lymphoma. CD19 CAR T cells were recently shown to strip CD19 from the surface of B cell lymphoma cell lines in a process called “trogocytosis,” however, the clinical relevance of this phenomenon remains poorly defined. The purpose of this study was to determine the impact of CD19 trogocytosis on CAR T cell escape in B cell lymphoma and the importance of CAR T cell affinity to trogocytosis mediated tumor escape. We cocultured CD19 CAR T cells with primary CLL, ALL, mantle cell lymphoma and diffuse large B cell lymphoma patient material and identified rapid loss of CD19 from the surface of the malignant cells in all subtypes. CD19 was also observed to be transferred from the lymphoma cell to CD19 CAR T cells, resulting in CAR T cell autoreactivity termed “fratricide.” We then utilized a recently developed low affinity CD19 CAR to assess the importance of CAR affinity in CD19 loss by trogocytosis. Coculture of low affinity CD19 CAR T cells revealed significantly reduced loss of CD19 by trogocytosis from several ALL cell lines and primary samples when compared to high affinity CD19 CAR T cells. Finally, in vivo analysis of CAR affinity revealed increased CAR T cell efficacy and persistence by low affinity CD19 CAR T cells when compared to high affinity CD19 CAR T cells in an established ALL mouse model. Taken together, these data demonstrate that loss of CD19 by CAR T cell mediated trogocytosis occurs in many B cell malignancies and can be ameliorated by modulation of CAR affinity, providing a possible avenue for more effective CAR T cell therapies in the clinic.
Immunotherapeutic effects of RCH-2 on glioblastoma through enhancing NK cellmediated cell lysis
Authors: Lin Yu-Ling , Lin Han-Huei 
Published: February 2023

Abstract
Glioblastoma is the most common and dangerous in primary brain tumors. Recent success in cancer immunotherapy is considered a breakthrough in cancer treatment. RCH-2, a phytocompound isolated from Larrea tridentata, is a transcriptional inhibitor of the Sp1 transcription factor. RCH-2 combined with different chemotherapeutic drugs also shows an excellent synergistic effect for cancer therapy in glioblastoma. RCH-2 effectively inhibits tumor growth in vivo, but less RCH-2 accumulated in the tumor area. RCH-2 might trigger an immune response to help tumor suppression. In this study, glioblastoma tumor-bearing mice were treated with RCH-2 daily by oral administration. Their cytokines and anti-tumor antibodies in sera were analyzed. Results showed that RCH-2 induced Th2 cytokines and promoted anti-tumor antibody production that efficiently induced antibody-dependent cell-mediated cytotoxicity (ADCC) to kill tumor cells. Our finding indicated that RCH-2 could induce more anti-tumor antibodies to efficiently target the tumor cell and trigger NK-mediated cell lysis.
Expanded ATLAS™-identified neoantigen-specific peripheral T cells (NPTs) demonstrate considerable neoantigen breadth, polyfunctionality, and effector function.
Authors: Perry James R , Reuter Mercay , DeVault Victoria L , Li Adrienne , Zope Harshal , DeOliveira Daniel B , Khare Pranay D , Jain Manish , Winstead Colleen J , Lam Hubert , Flechtner Jessica Baker 
Published: February 2023

Abstract
Adoptive T cell therapy using ex vivo expanded autologous tumor-infiltrating lymphocytes (TIL) has resulted in notable tumor regression across multiple solid tumor indications. Despite their success, TIL harvest requires invasive surgery and sterile isolation. In addition, extracted cells from an immunosuppressive tumor microenvironment (TME) often have impaired functions, low neoantigen-specificity and require high dose cytokine for expansion. All possible reasons for non-responders or post-treatment relapse. Generating T cell therapies specifically expanded against neoantigen targets and derived from peripheral blood lymphocytes may overcome these limitations.
The ATLAS bioassay identifies patient-specific neoantigen targets of T cells, and Inhibigens™, tumor antigens that are detrimental to protective immune responses. Using PLANET™, a robust and scalable closed manufacturing process, T cells specific for up to 30 ATLAS-identified neoantigens (excluding Inhibigens) are expanded, providing considerable breadth of tumor recognition and the potential to limit tumor escape. Use of peripheral T cells leverages robust cells not suppressed by the TME and eliminates the need for invasive tumor resection. Our data show that NPTs are specific for up to 89% of targeted neoantigens, consist of non-exhausted effector and central memory cells, and express proliferative and tissue homing markers. NPTs are highly polyfunctional, secreting multiple combinations of IFNγ, Granzyme B, TNFα, and MIP1α in response to specific neoantigens. Evaluation of markers for memory-progenitor stem-like features in NPTs are being explored and will be discussed. The TITAN™ clinical trial evaluating GEN-011 NPTs is ongoing (NCT04596033).
Fine-tuning Chimeric Antigen Receptor Signaling by Reducing CD3ζ ITAM Diversity
Authors: Majumdar Shubhabrata , Bettini Matthew L 
Published: February 2023

Abstract
One of the major challenges facing CAR based cancer immunotherapy is the lack of in vivo persistence of functional CAR T-cells due to low memory cell formation and exhaustion. Previous studies have suggested that strong TCR signaling favors the formation of terminally differentiated short-lived effector cells that get exhausted faster while weaker signaling favors formation of less differentiated memory-like cells. It was suggested that reducing CD3 ITAM (immunoreceptor tyrosine-based activation motif) sequence diversity while keeping the number of ITAMs same, attenuates TCR signaling strength to different extents, thus, highlighting the signaling non-redundancy of each individual ITAM sequence. Based on this, we designed 2nd generation murine anti-CD19 CARs with modified CD3ζ domains with the goals of optimizing CAR signaling and studying the non-redundant signaling properties of the individual ITAMs in the context of CARs. The CARs have either three copies of ζ1 ITAMs, ζ2 ITAMs or ζ3 ITAMs instead of the wildtype (WT) ζ1,2 and 3 together. We hypothesize that the non-redundancy of the individual ITAMs and the reduction in ITAM diversity will allow for optimization of CAR T cell signaling quantity, quality and improved T-cell persistence. The single flavor CAR expressing CD8+ T-cells can kill target CD19+ leukemia cells in vitro and are similar to the WT ζ CAR. Interestingly, we observe differences in short-term post-killing live T-cell counts. We also observe different levels of cytokine and perforin production by the activated T cells. When we look at their signaling, we observe differences in Erk, Akt and NFAT signaling. These signaling and functional differences open up the possibility of optimizing CAR persistence and function.
Adjuvanted bacteriophage vaccine targeting Pseudomonas aeruginosa
Authors: Román-Cruz Valery Cristina , Miller Shannon , Buhl Cassandra , Schooner Roman , Walsh Lois , Secor Patrick , Burkhart David , Evans Jay 
Published: February 2023

Abstract
Pseudomonas aeruginosa (Pa) is a Gram-negative bacterium which is associated with chronic diabetic wounds as well as potentially deadly lung infections in cystic fibrosis patients. Approximately 51,000 cases of Pa infections occur annually; of these cases, 13% are resistant to antibiotics which results in the deaths of ~400 individuals every year. Diversity between Pa strains presents a challenge in developing a vaccine or therapeutic capable of resolving infections caused by different strains. Pf phage (a filamentous bacteriophage) has been found in Pa from chronic diabetic wound isolates and has been show to increase virulence of Pa. Recent findings by our team indicate that a Pf phage-targeted vaccine or monoclonal antibody provide protection from the establishment of Pa infection in mice. To further improve this innovative new vaccine targeting Pa, adjuvant systems were used to enhance humoral response to the vaccine. A consensus peptide from Pf Phage coat protein was conjugated to the carrier protein CRM197 and combined with novel adjuvants and delivery systems. Selected adjuvants significantly enhanced humoral immunity to the Pf Phage peptide in a dose-dependent manner. Combination adjuvant systems were also used to further enhance antigen-specific immunity to Pf Phage and cell-mediated immunity to the carrier protein. The development of an adjuvanted Pf phage vaccine to protect against Pa infections is a new and innovative strategy with the potential to protect patients at risk for opportunistic bacterial infections.
Prefusion F-based polyanhydride nanovaccine induces robust humoral and cell-mediated immunity resulting in long-lasting protection against respiratory syncytial virus
Authors: Stephens Laura , Ross Kathleen A. , Legge Kevin L. , McLellan Jason S. , Narasimhan Balaji , Varga Steven M. 
Published: February 2023

Abstract
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children, accounting for 7% of deaths in those less than one year of age and leading to more than $300 million in annual medical costs. As natural exposure to the virus generates insufficient immunity, there is a critical need for a safe and efficacious vaccine to prevent RSV-induced disease. We developed an intranasal vaccine, termed RSVNanoVax, composed of polyanhydride nanoparticles encapsulating the RSV prefusion F protein and a CpG1668 oligodeoxynucleotide adjuvant. RSVNanoVax prime-boost vaccination of BALB/c mice induced RSV F-directed IgG serum antibodies specific for both site 0 and site II on the F protein. Systemic antibodies maintained a robust neutralizing capacity out to at least six months post-vaccination. Vaccination with RSVNanoVax also induced F-directed IgA titers within the lungs and nasal passages as well as lung tissue-resident memory CD4 and CD8 T cells, indicating that the vaccine established both a humoral and cell-mediated immune response within the mucosal tissues. Vaccination with RSVNanoVax resulted in protection from RSV-induced disease out to at least six months post-challenge, as measured by weight loss and pulmonary dysfunction. RSVNanoVax vaccination of outbred Swiss Webster mice also elicited protection from RSV-induced disease, and resulted in complete viral clearance as early as day two after RSV challenge. High RSV F-directed antibody titers were also observed in the serum of outbred mice. Based on the robust immune response and the high level of protection observed in both inbred and outbred populations, our prefusion RSV F nanoparticle formulation represents a promising RSV vaccine candidate.
Mucosal delivery of a polyanhydride nanovaccine incorporating CpG and the post-fusion F/ G proteins induces protective immunity against BRSV infection in neonatal calves.
Authors: Maina Teresia , Grego Elizabeth A , Sacco Randy E , Narasimhan Balaji , McGill Jodi L 
Published: February 2023

Abstract

Objective:
Previously, immunization with a single intranasal dose of a BRSV post-fusion F/G nanovaccine resulted in partial protection from a BRSV challenge (McGill et al. 2019, McGill et al. 2018). Knowledge gained from these previous studies was used to optimize the vaccine by incorporating CpG-ODN and to investigate the impact of mucosal vs. systemic vaccination routes. In this study a prime-boost immunization regimen was used.

Method:
36 neonatal, mixed-sex, Holstein calves were divided into 6 groups. Group 1 received a heterologous regime with saline and group 2 a homologous boost of the ‘empty’ nanovaccine CPG. Groups 3 and 4 received a homologous mucosal regime of the nanovaccine ± CpG, while groups 5 and 6 received a heterologous regime of the nanovaccine ± CpG. Vaccine-induced responses were monitored and 6 weeks after boost, all calves were challenged with BRSV. Nasopharyngeal swabs were collected for viral shedding and calves monitored for clinical signs and euthanized on day 7 after infection. Lungs were scored for gross pathology. Blood, nasal secretions and lung tissue samples were analyzed for BRSV specific immune responses.

Results:
Unvaccinated controls and CpG-only nanovaccine controls developed lung pathology consistent with a severe BRSV infection. We observed no evidence of vaccine enhanced disease in any vaccinated group. Calves that received the homologous vaccination of the nanovaccine + CPG had significantly less lung pathology and viral burden in the lungs compared to control calves.

Conclusions:
These results indicate that an intranasal homologous vaccination regimen with the post-fusion F/G + CpG nanovaccine has the capacity to reduce BRSV disease in neonatal calves with preexisting maternal antibodies.