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Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34479991


COVID-19 induces a robust, extended inflammatory "cytokine storm" that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNß directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNß reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNß/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.

Coronavirus/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/virologia , Macrófagos/metabolismo , Animais , COVID-19/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/genética , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais
Histopathology ; 78(4): 532-541, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32931028


AIMS: A varied spectrum of histopathological changes has been associated with immune checkpoint inhibitor (ICI) colitis. This study was performed to evaluate the prevalence of different histopathological patterns of injury in patients with ICI colitis and their association with specific immune check-point inhibitors. METHODS AND RESULTS: Biopsies from patients with clinically and histologically confirmed ICI colitis were reviewed blindly to determine the predominant pattern of injury and to quantitate discrete histological parameters using the Geboes score. Paneth cell metaplasia, intraepithelial lymphocytes, abnormal subepithelial collagen and degree of crypt epithelial apoptosis was also recorded. A total of 86 patients with ICI colitis (ipilimumab, n = 14; ipilimumab + nivolumab, n = 29; nivolumab, n = 20 and pembrolizumab, n = 23) were included. The patterns of injury identified included diffuse active colitis (n = 22), chronic active colitis (n = 22), lymphocytic colitis (LC, n = 16), collagenous colitis (CC, n = 14), graft-versus-host disease-like colitis (n = 7) and mixed colitis (n = 5). Patients on ipilimumab were more likely to have a diffuse active colitis pattern without features of chronicity (P < 0.01) and less likely to have LC (P < 0.05) compared to other ICIs. LC and CC were more common in patients on nivolumab and pembrolizumab relative to other groups (P < 0.05). Chronic active colitis was most frequent in nivolumab patients (P < 0.05), and these patients had received more ICI doses and had been on ICI treatment longer compared to other treatment groups. CONCLUSIONS: ICI colitis should be considered in the differential diagnosis of all the common inflammatory patterns of colitis and shows medication specific differences in patterns of injury.

Cancer ; 126(16): 3758-3767, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32567084


BACKGROUND: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.

Antígeno CTLA-4/genética , Colite/tratamento farmacológico , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Vitamina D/administração & dosagem , Idoso , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Colite/induzido quimicamente , Colite/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos/efeitos dos fármacos , Masculino , Melanoma/complicações , Melanoma/patologia , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
JCO Oncol Pract ; 16(9): e933-e942, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32401685


PURPOSE: Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn's disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis. METHODS: We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis. RESULTS: Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti-tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare. CONCLUSION: In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.

Colite Microscópica , Colite , Doenças Inflamatórias Intestinais , Colite Microscópica/induzido quimicamente , Humanos , Inibidores de Checkpoint Imunológico , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Estudos Retrospectivos
Inflamm Bowel Dis ; 26(12): 1933-1942, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-32115633


BACKGROUND: South Asians have recently been identified as having a rapidly rising incidence and prevalence of inflammatory bowel disease (IBD) throughout the world. However, longitudinal phenotypic studies of South Asians living in the United States remain scarce. METHODS: We retrospectively studied 171 South Asian patients with IBD treated at 2 US tertiary centers who presented between 2000 and 2016. South Asian IBD patients were randomly matched in a 1:2 ratio with sex and IBD subtype-matched (ulcerative colitis [UC] vs Crohn disease [CD]) white control patients (n = 342). Demographic and phenotypic characteristics were evaluated and compared between the 2 groups. Odds ratios (OR), logistic regression, and survival analysis were performed using R studio and STATA. RESULTS: 81 South Asian patients and 162 white patients had CD, and 90 South Asians and 180 white patients had UC. Among the CD group, South Asian patients were diagnosed at a median older age (age 28) than white patients (21 years; P < 0.003). Fistulizing disease (24.1% vs 8.6%; P < 0.002), perianal disease (20.3% vs 2.5%; P < 0.005), and presentation of rectal pain (16.2% vs 2.9%; P < 0.001) were more common among South Asian patients with CD than among white patients. After adjusting for covariates, South Asian patients with CD were less likely to be placed on thiopurines (OR = 0.36; P < 0.007) or to receive more than 1 biologic (OR = 0.42; P < 0.040). South Asian patients with UC were less likely to have proctitis (10% vs 22.2%; P < 0.022) and more likely to have primary sclerosing cholangitis (n = 7 vs n = 2; P < 0.007). South Asian patients born in the United States or those who had migrated before age 5 were younger at the age of IBD diagnosis (age 18.9 vs 32.4; P < 0.0005). CONCLUSION: We found unique demographic and phenotypic characteristics among South Asian patients, including more penetrating disease in those with CD and less proctitis among those with UC, along with altered medication use patterns. Distinct environmental exposures and a potentially unique genetic profile of South Asian patients may confer this variable phenotypic expression, influencing management of this increasingly at-risk population.