Dillon’s Publications

@article{hosni2024adipocyte,

title = {Adipocyte precursor-derived NRG1 promotes resistance to FGFR inhibition in urothelial carcinoma},

author = {Sana Hosni and Viola Kilian and Niklas Klümper and Daniela Gabbia and Katharina Sieckmann and Dillon Corvino and Anja Winkler and Miriam Saponaro and Karin Wörsdörfer and Doris Schmidt and others},

url = {https://doi.org/10.1158/0008-5472.CAN-23-1398},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {Cancer Research},

volume = {84},

number = {5},

pages = {725–740},

publisher = {American Association for Cancer Research},

abstract = {Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer in a paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3; also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared with their progenitors. Pharmacologic inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{corvino2024type,

title = {Type I Interferon Drives a Cellular State Inert to TCR-Stimulation and Could Impede Effective T-Cell Differentiation in Cancer},

author = {Dillon Corvino and Martin Batstone and Brett G M Hughes and Tim Kempchen and Susanna S Ng and Nazhifah Salim and Franziska Schneppenheim and Denise Rommel and Ananthi Kumar and Sally Pearson and others},

url = {https://doi.org/10.1002/eji.202451371},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {European Journal of Immunology},

pages = {e202451371},

abstract = {Background:

Head and neck squamous cell carcinoma (HNSCC) is linked to human papillomavirus (HPV) infection. HPV-positive and HPV-negative HNSCC exhibit distinct molecular and clinical characteristics. Although checkpoint inhibitors have shown efficiency in recurrent/metastatic HNSCC, response variability persists regardless of HPV status. This study aimed to explore the CD8+ T-cell landscape in HPV-negative HNSCC.



Methods:

We performed simultaneous single-cell RNA and TCR sequencing of CD8+ tumor-infiltrating lymphocytes (TILs) from treatment-naïve HPV-negative HNSCC patients. Additionally, cells were stimulated ex vivo, which allowed for the tracking of clonal transcriptomic responses.



Results:

Our analysis identified a subset of CD8+ TILs highly enriched for interferon-stimulated genes (ISG). TCR analysis revealed ISG cells are clonally related to a population of granzyme K (GZMK)-expressing cells. However, unlike GZMK cells, which exhibited rapid effector-like phenotypes following stimulation, ISG cells were transcriptionally inert. Additionally, ISG cells showed specific enrichment within tumor and were found across multiple tumor entities.



Conclusions:

ISG-enriched CD8+ TILs are a consistent feature of various tumor entities. These cells are poorly understood but possess characteristics that may impact antitumor immunity. Understanding the unique properties and functionality of ISG cells could offer innovative treatment approaches to improve patient outcomes in HPV-negative HNSCC and other cancer types.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{giordano2024rna,

title = {L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial},

author = {Frank A Giordano and Julian P Layer and Sonia Leonardelli and Lea L Friker and Roberta Turiello and Dillon Corvino and Thomas Zeyen and Christina Schaub and Wolf Müller and Elena Sperk and others},

url = {https://doi.org/10.1038/s41467-024-48416-9},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {Nature Communications},

volume = {15},

number = {1},

pages = {4210},

publisher = {Nature Publishing Group UK London},

abstract = {The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wang2023sting,

title = {STING activation promotes autologous type I interferon–dependent development of type 1 regulatory T cells during malaria},

author = {Yulin Wang and Fabian De Labastida Rivera and Chelsea L Edwards and Teija CM Frame and Jessica A Engel and Luzia Bukali and Jinrui Na and Susanna S Ng and Dillon Corvino and Marcela Montes De Oca and others},

url = {https://doi.org/10.1172/JCI169417},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {The Journal of Clinical Investigation},

volume = {133},

number = {19},

publisher = {American Society for Clinical Investigation},

abstract = {The development of highly effective malaria vaccines and improvement of drug-treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. The activation of STING in CD4+ T cells by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10– and IFN-γ–coproducing CD4+ T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. CD4+ T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by CD4+ T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{edwards202310,

title = {IL-10-producing Th1 cells possess a distinct molecular signature in malaria},

author = {Chelsea L Edwards and Susanna S Ng and Fabian Labastida Rivera and Dillon Corvino and Jessica A Engel and Marcela Montes Oca and Luzia Bukali and Teija CM Frame and Patrick T Bunn and Shashi Bhushan Chauhan and others},

url = {https://doi.org/10.1172/JCI153733},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {The Journal of clinical investigation},

volume = {133},

number = {1},

publisher = {American Society for Clinical Investigation},

abstract = {Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10–producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10–Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum–infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{saponaro2023cdcp1,

title = {CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression},

author = {Miriam Saponaro and Sina Flottmann and Markus Eckstein and Oliver Hommerding and Niklas Klümper and Dillon Corvino and Sana Hosni and Anja Schmidt and Nicolas Mönig and Doris Schmidt and others},

url = {https://doi.org/10.1038/s41598-022-26579-z},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Scientific Reports},

volume = {13},

number = {1},

pages = {73},

publisher = {Nature Publishing Group UK London},

abstract = {The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP1 is highly expressed in advanced UC, which significantly correlates with shorter overall survival. Importantly, the basal/squamous UC subtype showed significantly enriched CDCP1 at the mRNA and protein levels. The functional role of CDCP1 overexpression was assessed taking advantage of ex vivo organoids derived from the CDCP1pcLSL/+ transgenic mouse model. Furthermore, CDCP1 knockout UC cell lines were generated using CRISPR/Cas9 technology. Interestingly, CDCP1 overexpression significantly induced the activation of MAPK/ERK pathways in ex vivo organoids and increased their proliferation. Similarly, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK/ERK pathway activity reduction. Our results highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role, suggesting that targeting CDCP1 could be a rational therapeutic strategy for the treatment of advanced UC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{corvino2023stressed,

title = {Stressed out: NKp46 binds ecto-calreticulin.},

author = {Dillon Corvino and Denise Rommel and Franziska Schneppenheim and Tobias Bald},

url = {https://doi.org/10.1111/imcb.12659},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Immunology and Cell Biology},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{casey2023regulatory,

title = {Regulatory T cells hamper the efficacy of T-cell engaging bispecific antibody therapy},

author = {Mika Casey and Carol Lee and Wing Yu Kwok and Soi Cheng Law and Dillon Corvino and Maher K Gandhi and Simon J Harrison and Kyohei Nakamura},

url = {https://doi.org/10.3324/haematol.2023.283758},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Haematologica},

abstract = {T-cell-engaging bispecific antibodies (T-BsAb) have produced impressive clinical responses in patients with relapsed/refractory B-cell malignancies, although treatment failure remains a major clinical challenge. Growing evidence suggests that a complex interplay between immune cells and tumor cells is implicated in the mechanism of action and therefore, understanding immune regulatory mechanisms might provide a clue for how to improve the efficacy of T-BsAb therapy. Here, we investigated the functional impact of regulatory T (Treg) cells on anti-tumor immunity elicited by T-BsAb therapy. In a preclinical model of myeloma, the activation and expansion of Treg cells in the bone marrow were observed in response to anti-B-cell maturation antigen (BCMA) T-BsAb therapy. T-BsAb triggered the generation of induced Treg cells from human conventional CD4 cells after co-culture with tumor cells. Moreover, T-BsAb directly activated freshly isolated circulating Treg cells, leading to the production of interleukin-10 and inhibition of T-BsAb-mediated CD8 T-cell responses. The activation of Treg cells was also seen in bone marrow samples from myeloma patients after ex vivo treatment with T-BsAb, further supporting that T-BsAb have an impact on Treg homeostasis. Importantly, transient ablation of Treg cells in combination with T-BsAb therapy dramatically improved effector lymphocyte activities and disease control in the preclinical myeloma model, leading to prolonged survival. Together, this information suggests that therapy-induced activation of Treg cells critically regulates anti-tumor immunity elicited by T-BsAb therapy, with important implications for improving the efficacy of such treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{edwards2023molecular,

title = {A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases},

author = {Chelsea L Edwards and Jessica A Engel and Fabian Labastida Rivera and Susanna S Ng and Dillon Corvino and Marcela Montes Oca and Teija CM Frame and Shashi Bhushan Chauhan and Siddharth Sankar Singh and Awnish Kumar and others},

url = {https://insight.jci.org/articles/view/169362},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {JCI insight},

volume = {8},

number = {24},

publisher = {American Society for Clinical Investigation},

abstract = {Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell–autologous mechanism to prevent such damage. However, IL-10–producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{li2022nkg7,

title = {NKG7 Is Required for Optimal Antitumor T-cell Immunity},

author = {Xian-Yang Li and Dillon Corvino and Bianca Nowlan and Amelia Roman Aguilera and Susanna S Ng and Matthias Braun and Anthony R Cillo and Tobias Bald and Mark J Smyth and Christian R Engwerda},

url = {https://doi.org/10.1158/2326-6066.CIR-20-0649},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Cancer Immunology Research},

volume = {10},

number = {2},

pages = {154–161},

publisher = {American Association for Cancer Research},

abstract = {Tumor antigen-specific CD8+ T cells play a critical role in antitumor immunity. Clinical trials reinvigorating the immune system via immune checkpoint blockade (ICB) have shown remarkable clinical promise. Numerous studies have identified an association between NKG7 expression and patient outcome across different malignancies. However, aside from these correlative observations, very little is known about NKG7 and its role in antitumor immunity. Herein, we utilized single-cell RNA sequencing (scRNA-seq) datasets, NKG7-deficient mice, NKG7-reporter mice, and mouse tumor models to investigate the role of NKG7 in neoantigen-mediated tumor rejection and ICB immunotherapy. scRNA-seq of tumors from patients with metastatic melanoma or head and neck squamous cell carcinoma revealed that NKG7 expression is highly associated with cytotoxicity and specifically expressed by CD8+ T cells and natural killer (NK) cells. Furthermore, we identified a key role for NKG7 in controlling intratumor T-cell accumulation and activation. NKG7 was upregulated on intratumor antigen-specific CD8+ T cells and NK cells and required for the accumulation of T cells in the tumor microenvironment. Accordingly, neoantigen-expressing mouse tumors grew faster in Nkg7-deficient mice. Strikingly, efficacy of single or combination ICB was significantly reduced in Nkg7-deficient mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{corvino2022plasticity,

title = {Plasticity of NK cells in Cancer},

author = {Dillon Corvino and Ananthi Kumar and Tobias Bald},

url = {https://doi.org/10.3389/fimmu.2022.888313},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Frontiers in Immunology},

volume = {13},

pages = {888313},

publisher = {Frontiers Media SA},

abstract = {Natural killer (NK) cells are crucial to various facets of human immunity and function through direct cytotoxicity or via orchestration of the broader immune response. NK cells exist across a wide range of functional and phenotypic identities. Murine and human studies have revealed that NK cells possess substantial plasticity and can alter their function and phenotype in response to external signals. NK cells also play a critical role in tumor immunity and form the basis for many emerging immunotherapeutic approaches. NK cells can directly target and lyse malignant cells with their inherent cytotoxic capabilities. In addition to direct targeting of malignant cells, certain subsets of NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) which is integral to some forms of immune checkpoint-blockade immunotherapy. Another important feature of various NK cell subsets is to co-ordinate anti-tumor immune responses by recruiting adaptive and innate leukocytes. However, given the diverse range of NK cell identities it is unsurprising that both pro-tumoral and anti-tumoral NK cell subsets have been described. Here, NK cell subsets have been shown to promote angiogenesis, drive inflammation and immune evasion in the tumor microenvironment. To date, the signals that drive tumor-infiltrating NK cells towards the acquisition of a pro- or anti-tumoral function are poorly understood. The notion of tumor microenvironment-driven NK cell plasticity has substantial implications for the development of NK-based immunotherapeutics. This review will highlight the current knowledge of NK cell plasticity pertaining to the tumor microenvironment. Additionally, this review will pose critical and relevant questions that need to be addressed by the field in coming years.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{singh2022increased,

title = {Increased amphiregulin expression by CD4+ T cells from individuals with asymptomatic Leishmania donovani infection},

author = {Siddharth Sankar Singh and Shashi Bhushan Chauhan and Susanna S Ng and Dillon Corvino and Fabian Labastida Rivera and Jessica A Engel and Nic Waddell and Pamela Mukhopadhay and Rebecca L Johnston and Lambros T Koufariotis and others},

url = {https://doi.org/10.1002/cti2.1396},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Clinical & Translational Immunology},

volume = {11},

number = {6},

pages = {e1396},

abstract = {Objectives

There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients.



Methods

CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated.



Results

Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T-cell subsets in asymptomatic individuals.



Conclusion

Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{seier2021druggable,

title = {Druggable epigenetic suppression of interferon-induced chemokine expression linked to MYCN amplification in neuroblastoma},

author = {Johanna A Seier and Julia Reinhardt and Kritika Saraf and Susanna S Ng and Julian P Layer and Dillon Corvino and Kristina Althoff and Frank A Giordano and Alexander Schramm and Matthias Fischer and others},

url = {https://doi.org/10.1136/jitc-2020-001335},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Journal for ImmunoTherapy of Cancer},

volume = {9},

number = {5},

publisher = {BMJ Publishing Group},

abstract = {Background Amplification of the MYCN oncogene is a molecular hallmark of aggressive neuroblastoma (NB), a childhood cancer of the sympathetic nervous system. There is evidence that MYCN promotes a non-inflamed and T-cell infiltration-poor (‘cold’) tumor microenvironment (TME) by suppressing interferon signaling. This may explain, at least in part, why patients with NB seem to have little benefit from single-agent immune checkpoint blockade (ICB) therapy. Targeting MYCN or its effectors could be a strategy to convert a cold TME into a ‘hot’ (inflamed) TME and improve the efficacy of ICB therapy.



Methods NB transcriptome analyses were used to identify epigenetic drivers of a T-cell infiltration-poor TME. Biological and molecular responses of NB cells to epigenetic drugs and interferon (IFN)-γ exposure were assessed by proliferation assays, immunoblotting, ELISA, qRT-PCR, RNA-seq and ChIP-qPCR as well as co-culture assays with T cells.



Results We identified H3K9 euchromatic histone-lysine methyltransferases EHMT2 and EHMT1, also known as G9a and GLP, as epigenetic effectors of the MYCN-driven malignant phenotype and repressors of IFN-γ transcriptional responses in NB cells. EHMT inhibitors enhanced IFN-γ-induced expression of the Th1-type chemokines CXCL9 and CXCL10, key factors of T-cell recruitment into the TME. In MYCN-amplified NB cells, co-inhibition of EZH2 (enhancer of zeste homologue 2), a H3K27 histone methyltransferase cooperating with EHMTs, was needed for strong transcriptional responses to IFN-γ, in line with histone mark changes at CXCL9 and CXCL10 chemokine gene loci. EHMT and EZH2 inhibitor response gene signatures from NB cells were established as surrogate measures and revealed high EHMT and EZH2 activity in MYCN-amplified high-risk NBs with a cold immune phenotype.



Conclusion Our results delineate a strategy for targeted epigenetic immunomodulation of high-risk NBs, whereby EHMT inhibitors alone or in combination with EZH2 inhibitors (in particular, MYCN-amplified NBs) could promote a T-cell-infiltrated TME via enhanced Th1-type chemokine expression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ambalathingal2020proteome,

title = {Proteome-wide analysis of T-cell response to BK polyomavirus in healthy virus carriers and kidney transplant recipients reveals a unique transcriptional and functional profile},

author = {George R Ambalathingal and Ross S Francis and Dillon Corvino and Sriganesh Srihari and Blake T Aftab and Corey Smith and Rajiv Khanna},

url = {https://doi.org/10.1002/cti2.1102},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Clinical & Translational Immunology},

volume = {9},

number = {1},

pages = {e01102},

abstract = {Objectives

Cellular immunity against BK polyomavirus (BKV)-encoded antigens plays a crucial role in long-term protection against virus-associated pathogenesis in transplant recipients. However, in-depth understanding on dynamics of these cellular immune responses is required to develop better immune monitoring and immunotherapeutic strategies.



Methods

Here, we have conducted a proteome-wide analysis of BKV-specific T-cell responses in a cohort of 53 healthy individuals and 26 kidney transplant recipients to delineate the functional and transcriptional profile of these effector cells and compared these characteristics to T cells directed against cytomegalovirus, which is also known to cause significant morbidity in transplant recipients.



Results

Profiling of BKV-specific CD4+ and CD8+ T cells revealed that kidney transplant recipients with high levels of circulating viraemia showed significantly reduced T-cell reactivity against large T and/or small T antigens when compared to healthy donors. Interestingly, T cells specific for these antigens showed strong cross-recognition to orthologous JC virus (JCV) peptides, including those exhibiting varying degrees of sequence identity. Ex vivo functional and phenotypic characterisation revealed that the majority of BKV-specific T cells from renal transplant recipients expressed low levels of the key transcriptional regulators T-bet and eomesodermin, which was coincident with undetectable expression of granzyme B and perforin. However, in vitro stimulation of T cells with BKV epitopes selectively enhanced the expression of T-bet, granzyme B and cellular trafficking molecules (CCR4, CD49d and CD103) with minimal change in eomesodermin and perforin.



Conclusions

These observations provide an important platform for the future development of immune monitoring and adoptive T-cell therapy strategies for BKV-associated diseases in transplant recipients, which may also be exploited for similar therapeutic value in JCV-associated clinical complications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{braun2020cd155,

title = {CD155 on tumor cells drives resistance to immunotherapy by inducing the degradation of the activating receptor CD226 in CD8+ T cells},

author = {Matthias Braun and Amelia Roman Aguilera and Ashmitha Sundarrajan and Dillon Corvino and Kimberley Stannard and Sophie Krumeich and Indrajit Das and Luize G Lima and Lizeth G Meza Guzman and Kunlun Li and others},

url = {https://doi.org/10.1016/j.immuni.2020.09.010},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Immunity},

volume = {53},

number = {4},

pages = {805–823},

publisher = {Elsevier},

abstract = {The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kumar2020type,

title = {Type I interferons suppress anti-parasitic immunity and can be targeted to improve treatment of visceral leishmaniasis},

author = {Rajiv Kumar and Patrick T Bunn and Siddharth Sankar Singh and Susanna S Ng and Marcela Montes Oca and Fabian De Labastida Rivera and Shashi Bhushan Chauhan and Neetu Singh and Rebecca J Faleiro and Chelsea L Edwards and others},

url = {https://doi.org/10.1016/j.celrep.2020.01.099},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Cell reports},

volume = {30},

number = {8},

pages = {2512–2525},

publisher = {Elsevier},

abstract = {Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4+ T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ng2020nk,

title = {The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation},

author = {Susanna S Ng and Fabian De Labastida Rivera and Juming Yan and Dillon Corvino and Indrajit Das and Ping Zhang and Rachel Kuns and Shashi Bhushan Chauhan and Jiajie Hou and Xian-Yang Li and others},

url = {https://doi.org/10.1038/s41590-020-0758-6},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Nature immunology},

volume = {21},

number = {10},

pages = {1205–1218},

publisher = {Nature Publishing Group US New York},

abstract = {Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria—two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{smith2019t,

title = {T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response},

author = {Corey Smith and Dillon Corvino and Leone Beagley and Sweera Rehan and Michelle A Neller and Pauline Crooks and Katherine K Matthews and Matthew Solomon and Laetitia Le Texier and Scott Campbell and others},

url = {https://doi.org/10.1172/JCI128323},

year  = {2019},

date = {2019-01-01},

urldate = {2019-01-01},

journal = {The Journal of clinical investigation},

volume = {129},

number = {11},

pages = {5020–5032},

publisher = {American Society for Clinical Investigation},

abstract = {BACKGROUND. Impaired T cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients.



METHODS. In the present study, we used high-throughput T cell receptor Vβ sequencing and T cell functional profiling to delineate the impact of ACT on T cell repertoire remodeling in the context of pretherapy immunity and ACT products.



RESULTS. These analyses indicated that a clinical response was coincident with significant changes in the T cell receptor Vβ landscape after therapy. This restructuring was associated with the emergence of effector memory T cells in responding patients, while nonresponders displayed dramatic pretherapy T cell expansions with minimal change following ACT. Furthermore, immune reconstitution included both adoptively transferred clonotypes and endogenous clonotypes not detected in the ACT products.



CONCLUSION. These observations demonstrate that immune control following ACT requires significant repertoire remodeling, which may be impaired in nonresponders because of the preexisting immune environment. Immunological interventions that can modulate this environment may improve clinical outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{edwards2018early,

title = {Early changes in CD4+ T-cell activation during blood-stage Plasmodium falciparum infection},

author = {Chelsea L Edwards and Susanna S Ng and Dillon Corvino and Marcela Montes de Oca and Fabian Labastida Rivera and Katia Nones and Vanessa Lakis and Nicola Waddell and Fiona H Amante and James S McCarthy and others},

url = {https://doi.org/10.1093/infdis/jiy281},

year  = {2018},

date = {2018-01-01},

urldate = {2018-01-01},

journal = {The Journal of Infectious Diseases},

volume = {218},

number = {7},

pages = {1119–1129},

publisher = {Oxford University Press US},

abstract = {We examined transcriptional changes in CD4+ T cells during blood-stage Plasmodium falciparum infection in individuals without a history of previous parasite exposure. Transcription of CXCL8 (encoding interleukin 8) in CD4+ T cells was identified as an early biomarker of submicroscopic P. falciparum infection, with predictive power for parasite growth. Following antiparasitic drug treatment, a CD4+ T-cell regulatory phenotype developed. PD1 expression on CD49b+CD4+ T (putative type I regulatory T) cells after drug treatment negatively correlated with earlier parasite growth. Blockade of PD1 but no other immune checkpoint molecules tested increased interferon γ and interleukin 10 production in an ex vivo antigen-specific cellular assay at the peak of infection. These results demonstrate the early development of an immunoregulatory CD4+ T-cell phenotype in blood-stage P. falciparum infection and show that a selective immune checkpoint blockade may be used to modulate early developing antiparasitic immunoregulatory pathways as part of malaria vaccine and/or drug treatment protocols.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}