Papers by Chyi-Chia R Lee
Journal of Clinical Investigation
Background: Head and neck squamous cell carcinoma not associated with human papillomavirus (HPV-u... more Background: Head and neck squamous cell carcinoma not associated with human papillomavirus (HPV-unrelated HNSCC) is associated with high rates of recurrence and poor survival. Methods: We conducted a clinical trial in 14 patients with newly diagnosed, HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death-ligand 1 (PD-L1) and neutralizes transforming growth factor-beta (TGF-). Results: Bintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses were observed and 12 of 14 patients (86%) were alive and disease free at one year. Alterations in regulatory T cell infiltration and spatial distribution relative to proliferating CD8 T cells indicated reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not viral-specific responses, correlated with development of a pathologic response. Detection of neoepitope-specific responses and pathologic responses in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pretreatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF- blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multi-mechanism neoadjuvant immunotherapy in patients with HPV-unrelated HNSCC. Conclusion: Our studies provide new insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant-specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced anti-tumor immunity following such treatment.
Science, 2021
Type 1 immunity gives fungi a foothold Type 17 immune responses play a vital role against fungal ... more Type 1 immunity gives fungi a foothold Type 17 immune responses play a vital role against fungal infections of the mucosa. It remains unclear whether other types of immune responses can also contribute to host defense against these pathogens. The yeast Candida albicans prominently infects patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), an inherited disease caused by loss-of-function mutations in the AIRE gene. Break et al. report that the oral susceptibility of Aire -deficient mice to C. albicans is not due to aberrant type 17 responses. Rather, the overproduction of interferon-γ by local CD4 + and CD8 + T cells in these mice disrupts the epithelial barrier, which increases susceptibility to C. albicans invasion. Similar type 1 immune pathways are operational in APECED patients. Inhibition of interferon-γ or the JAK-STAT signaling pathway in mice ameliorates disease symptoms, suggesting potential future therapeutic interventions for certain cla...
Histopathology, 2021
Fibrous cephalic plaques (FCPs) in individuals with tuberous sclerosis complex (TSC) may be excis... more Fibrous cephalic plaques (FCPs) in individuals with tuberous sclerosis complex (TSC) may be excised for cosmetic reasons or biopsied to confirm lesion identification and TSC diagnosis. The aim of this study was to determine the range of histopathological features of FCPs.
Annals of Clinical and Laboratory Research, 2015
Background: Large cell calcifying sertoli cell tumor (LCCSCT) is an exceedingly rare lesion of th... more Background: Large cell calcifying sertoli cell tumor (LCCSCT) is an exceedingly rare lesion of the testicle. It is most often seen in patients with Carney complex (CNC) or Peutz-Jeghers syndrome (PJS). We now report the first pediatric patient with what appears to be bilateral LCCSCT and no other conditions or a genetic syndrome, such as PJS or CNC, have been associated with it. Methods: A 10-year-old boy was found to have a right testicular mass during a routine pediatric examination; he underwent right orchiectomy. He was then evaluated clinically for PJS or CNC and underwent genetic testing. His tumor was studied by immunohistochemistry for the expression of calretinin, NY-ESO-1, inhibin, CD99, S100, PLAP, AE1/AE3, Bcl-2, p53, and Mib1. Results: Patient did not have clinical features or genetic abnormalities of CNC and PJS. Microscopic features showed large, round or cubical intratubular and aggregated tumor cells with prominent nuclear atypia, large and prominent nucleoli and extensive calcification. In the Immunohistochemical studies, calretinin and inhibin alpha were up regulated in LCCSCT as compared to the adjacent benign Sertoli cells. Meanwhile, NY-ESO-1 and CD99 were down-regulated in LCCSCT. Focally and weakly positive S100 was found in the tumor tissue, but no S100 expression was present in the adjacent Sertoli cells. There was no expression of PLAP, P53, Bcl-2, Mib1 and AE1/AE3 in LCCSCT and adjacent Sertoli cells. Micro-calcifications were found in the other gonad by ultrasonography, suggesting LCCSCT. Conclusion: LCCSCT is a rare testicular neoplasm, and may present in isolated rather than in more typical association with syndromes such as CNC and PJS.
Journal of Allergy and Clinical Immunology, 2019
a lower molecular weight band of approximately 437 bp was identified in cDNA from the patient's B... more a lower molecular weight band of approximately 437 bp was identified in cDNA from the patient's BLCLs. Sanger sequencing demonstrated abnormal splicing in the patient's cDNA amplicon, resulting in deletion of exon 13 and in-frame splicing of exons 12 and 14 (Fig 1, C). Immunoblotting of lysates from BLCLs demonstrated abrogation of STAT2 protein expression in our patient without expression of any truncated protein products (Fig 1, D). STAT2 deficiency in human subjects and mice is characterized by defective type I interferon signaling. 1,2,7 The infection and subsequent transformation of B cells with EBV activates STAT2 and upregulates expression of interferon-stimulated genes, including IFIT1, ISG15, and IRF7, which are further increased after exposure to type I interferons. 8,9 Expression of IFIT1, ISG15, and IRF7 was severely decreased in the patient's BLCLs compared with those from control subjects (time 0 in Fig 1, E). Furthermore, the patient's BLCLs did not upregulate IFIT1, ISG15, and IRF7 after IFN-a stimulation (Fig 1, E), indicating a lack of STAT2-driven signaling in response to type I interferons. Mouse models of STAT2 deficiency have demonstrated defective responses to viral infections both in vitro and in vivo. 1 Human STAT2 deficiency has been associated with development of recurrent and severe viral illnesses. After measles, mumps, and rubella vaccination, 1 patient had disseminated vaccine-strain measles virus, 1 another patient had meningitis with vaccine-strain mumps virus, 7 and 4 patients had post-measles, mumps, and rubella vaccine febrile syndromes with negative viral study results. 1,2,7 This is the first report of HLH in association with STAT2 deficiency. We identified a novel STAT2 variant in our patient, resulting in abrogation of protein expression and type I interferon response. This report, as well as previously published reports of patients with defects in STAT1 and IFNGR2, demonstrate that secondary HLH can occur with defects in either type I or type II interferon signaling. 4,5 The rapid improvement of our patient after high-dose IVIG suggests the utility of this intervention in treating secondary HLH triggered by infection. The beneficial effect of IVIG might be ascribed to passive immunization and possibly to its potential anti-inflammatory effect. Our report and other literature 2 suggests patients with STAT2 deficiency might benefit from monthly immunoglobulin replacement during childhood, particularly if they have received live vaccines before their molecular diagnosis, until their adaptive immune systems mature.
The Journal of investigative dermatology, 2018
Antimicrobial Agents and Chemotherapy, 2016
Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality... more Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in Candida -infected mice. Here, we found that treatment of immunocompetent Candida -infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury.
The Japanese Journal of Urology, 1998
Scientific Reports, 2017
Delayed diagnosis in invasive aspergillosis (IA) contributes to its high mortality. Gliotoxin (GT... more Delayed diagnosis in invasive aspergillosis (IA) contributes to its high mortality. Gliotoxin (GT) and bismethyl-gliotoxin (bmGT) are secondary metabolites produced by Aspergillus during invasive, hyphal growth and may prove diagnostically useful. Because IA pathophysiology and GT's role in virulence vary depending on the underlying host immune status, we hypothesized that GT and bmGT production in vivo may differ in three mouse models of IA that mimic human disease. We defined temporal kinetics of GT and bmGT in serum, bronchoalveolar lavage fluid (BALF) and lungs of A. fumigatus-infected chronic granulomatous disease (CGD), hydrocortisone-treated, and neutropenic mice. We harvested lungs for assessment of fungal burden, histology and GT/bmGT biosynthetic genes' mRNA induction. GT levels were higher in neutropenic versus CGD or steroid-treated lungs. bmGT was persistently detected only in CGD lungs. GT, but not bmGT, was detected in 71% of sera and 50% of BALF of neutropenic mice; neither was detected in serum/BALF of CGD or steroid-treated mice. Enrichment of GT in Aspergillusinfected neutropenic lung correlated with fungal burden and hyphal length but not induction of GT biosynthetic genes. In summary, GT is detectable in mouse lungs, serum and BALF during neutropenic IA, suggesting that GT may be useful to diagnose IA in neutropenic patients.
PloS one, 2016
Hermansky-Pudlak Syndrome type-1 (HPS-1) is an autosomal recessive disorder caused by mutations i... more Hermansky-Pudlak Syndrome type-1 (HPS-1) is an autosomal recessive disorder caused by mutations in HPS1 which result in reduced expression of the HPS-1 protein, defective lysosome-related organelle (LRO) transport and absence of platelet delta granules. Patients with HPS-1 exhibit oculocutaneous albinism, colitis, bleeding and pulmonary fibrosis postulated to result from a dysregulated immune response. The effect of the HPS1 mutation on human mast cells (HuMCs) is unknown. Since HuMC granules classify as LROs along with platelet granules and melanosomes, we set out to determine if HPS-1 cutaneous and CD34+ culture-derived HuMCs have distinct granular and cellular characteristics. Cutaneous and cultured CD34+-derived HuMCs from HPS-1 patients were compared with normal cutaneous and control HuMCs, respectively, for any morphological and functional differences. One cytokine-independent HPS-1 culture was expanded, cloned, designated the HP proMastocyte (HPM) cell line and characterized....
Neurology, Jan 3, 2016
To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multipl... more To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multiple sclerosis treated with daclizumab high-yield process (DAC-HYP). A total of 31 participants in an institutional review board-approved open-label phase I study of DAC-HYP (NCT01143441) were prospectively evaluated over 42 months for development of cutaneous AEs. Participants provided written informed consent. Fifteen participants were naive to anti-CD25 therapy (cohort B), while 16 had received daclizumab (Zenapax; Hoffmann-La Roche) IV for 4-9 years (mean 5.8 years) prior to enrollment (cohort A). Immunohistochemistry was performed on pretreatment and posttreatment skin biopsies of normal-appearing skin (cohort B only) and on lesional biopsies in participants presenting with rash (both cohorts). Cutaneous AEs occurred in 77% of patients, the majority presenting with patches of eczema requiring no treatment. Moderate to severe rash developed in 6 participants (19%) and required discontin...
The New England journal of medicine, Jan 3, 2016
Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestat... more Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).
Clinical Cancer Research, 2015
Purpose: Uveal melanoma is a rare melanoma variant with no effective therapies once metastases de... more Purpose: Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma. Experimental Design: We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing. Results: Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation ...
The p63 gene shows remarkable structural similarity to the p53 and p73 genes. Because of two prom... more The p63 gene shows remarkable structural similarity to the p53 and p73 genes. Because of two promoters, the p63 gene generates two types of protein isoforms, TAp63 and Np63. Each type yields three isotypes (, , ) because of differential splicing of the p63 COOH terminus. The pur- pose of this study was to determine whether there is a functional
Open Journal of Clinical Diagnostics, 2013
Von Hippel-Lindau (VHL) is an inherited neoplasia syndrome caused by inactivation of the VHL tumo... more Von Hippel-Lindau (VHL) is an inherited neoplasia syndrome caused by inactivation of the VHL tumor suppressor gene, characterized by the development of sporadic clear cell renal carcinoma, pheochromocytomas, retinal angioma, pancreatic cysts, and CNS hemangioblastomas. Glomeruloid hemangioma is a vascular lesion, previously considered to be specifically associated with POEMS (polyneuropathy, organomegaly, endocrinopathy/edema, M-protein and skin abnormalities) syndrome. However, there are reports of solitary glomeruloid hemangioma in patients without POEMS syndrome. We report the case of a 39-year-old male with VHL disease, with known bilateral clear cell renal carcinomas, CNS hemangioblastoma and pancreatic cysts. The patient presented with a 0.35 cm red papule on the left lateral neck, which was easily irritated, and bleed frequently. Histopathologically, there were irregular areas of ectatic vascular channels of small capillaries, resembling renal glomeruli, surrounded by actin-positive pericytes, within the dermis. These findings were consistent with a glomeruloid hemangioma. Fluorescent in-situ hybridization studies confirmed a deletion in the 3p25.3 region. As per clinical tests, no evidence of POEMS syndrome was found in this patient. Only six reports of glomeruloid hemangioma have been previously reported in patients without POEMS syndrome and this constitutes the first report of glomeruloid hemangioma in a patient with VHL.
Pigment Cell & Melanoma Research, 2013
Melanoma represents a significant malignancy in humans and dogs. Different from genetically engin... more Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model.
Acta neuropathologica communications, Jan 8, 2013
To investigate the association of DNA nucleotide excision repair (NER) defects with neurological ... more To investigate the association of DNA nucleotide excision repair (NER) defects with neurological degeneration, cachexia and cancer, we performed autopsies on 4 adult xeroderma pigmentosum (XP) patients with different clinical features and defects in NER complementation groups XP-A, XP-C or XP-D. The XP-A (XP12BE) and XP-D (XP18BE) patients exhibited progressive neurological deterioration with sensorineural hearing loss. The clinical spectrum encompassed severe cachexia in the XP-A (XP12BE) patient, numerous skin cancers in the XP-A and two XP-C (XP24BE and XP1BE) patients and only few skin cancers in the XP-D patient. Two XP-C patients developed internal neoplasms including glioblastoma in XP24BE and uterine adenocarcinoma in XP1BE. At autopsy, the brains of the 44 yr XP-A and the 45 yr XP-D patients were profoundly atrophic and characterized microscopically by diffuse neuronal loss, myelin pallor and gliosis. Unlike the XP-A patient, the XP-D patient had a thickened calvarium, and ...
Pigment Cell & Melanoma Research, 2014
We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repai... more We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological This article is a U.S. Government work and is in the public domain in the USA.
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Papers by Chyi-Chia R Lee