Dillon Corvino, PhD

@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}

}