RESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma worldwide, accounting for up to 40% of new non-Hodgkin Lymphoma (NHL) globally. People living with HIV are up to 17 times more likely to develop NHL, and as such, DLBCL is the leading cause of cancer death in this high-risk population. While histologically indistinguishable, HIV-associated (HIV+) and HIV-negative (HIV-) DLBCL are molecularly distinct, and biological differences may have implications for the development of future therapeutic interventions. Further, the impact of immunologic differences in people with HIV, including preceding ART, remains largely unknown. Here, we investigate the impact of HIV infection and ART exposure on the clinical features of DLBCL and T-cell immune response by performing imaging mass cytometry on our unique patient cohort in Malawi. In this cohort, HIV infection is positively prognostic, and HIV+/ART-naïve patients have the best outcomes. No established biomarkers other than Ki67 are associated with HIV or ART status, and the only tumour-intrinsic biomarkers that remain prognostic are MYC and MYC/BCL2 protein co-expression. Finally, TCR clonality is associated with distinct tumour-T cell interactions by HIV/ART status, indicating differential anti-tumour immune responses. We demonstrate previously undescribed HIV and ART-related differences in the DLBCL tumour microenvironment.
Assuntos
Infecções por HIV , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Linfócitos T/imunologia , Antirretrovirais/uso terapêuticoRESUMO
Quantitative metrics for vaccine-induced T-cell responses are an important need for developing correlates of protection and their use in vaccine-based medical management and population health. Molecular TCR analysis is an appealing strategy but currently requires a targeted methodology involving complex integration of ex vivo data (antigen-specific functional T-cell cytokine responses and TCR molecular responses) that uncover only public antigen-specific metrics. Here, we describe an untargeted private TCR method that measures breadth and depth metrics of the T-cell response to vaccine challenge using a simple pre- and post-vaccine subject sampling, TCR immunoseq analysis, and a bioinformatic approach using self-organizing maps and GLIPH2. Among 515 subjects undergoing SARS-CoV-2 mRNA vaccination, we found that breadth and depth metrics were moderately correlated between the targeted public TCR response and untargeted private TCR response methods. The untargeted private TCR method was sufficiently sensitive to distinguish subgroups of potential clinical significance also observed using public TCR methods (the reduced T-cell vaccine response with age and the paradoxically elevated T-cell vaccine response of patients on anti-TNF immunotherapy). These observations suggest the promise of this untargeted private TCR method to produce T-cell vaccine-response metrics in an antigen-agnostic and individual-autonomous context.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , SARS-CoV-2 , Sítios de Ligação de Anticorpos , Inibidores do Fator de Necrose Tumoral , Linfócitos T CD8-Positivos , COVID-19/prevenção & controle , Vacinação , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
BACKGROUND: Patients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options. METHODS: The efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO. RESULTS: In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64-2.14]). The probability of being event-free (progression-free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%). CONCLUSION: Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD-directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors.
Assuntos
Inotuzumab Ozogamicina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , RecidivaRESUMO
This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.
Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Citarabina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Análise de Sobrevida , Resultado do TratamentoRESUMO
Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination.
Assuntos
COVID-19 , SARS-CoV-2 , Vacinas contra COVID-19 , Feminino , Humanos , RNA Mensageiro , VacinaçãoRESUMO
Attaining complete remission of acute lymphoblastic leukemia (ALL) before hematopoietic stem cell transplantation (HSCT) correlates with better post-transplant outcomes. Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, has shown significantly higher rates of remission, minimal residual disease negativity, and HSCT versus standard chemotherapy in treating relapsed/refractory (R/R) ALL. We investigated the role of previous transplant and proceeding directly to HSCT after remission as factors in determining post-transplant survival in the setting of InO treatment for R/R ALL. The analyzed population comprised InO-treated patients who proceeded to allogeneic HSCT in 2 clinical trials (phase 1/2: NCT01363297 and phase 3: NCT01564784). Overall survival (OS) was defined as time from HSCT to death (any cause). Of 236 InO-treated patients, 101 (43%) proceeded to allogeneic HSCT and were included in this analysis. Most received InO as first salvage (62%); 85% had no previous HSCT. Median (95% confidence interval [CI]) post-transplant OS was 9.2 months (5.1, not evaluable) with 2-year survival probability (95% CI) of 41% (32% to 51%). In first-HSCT patients (nâ¯=â¯86), median (95% CI) post-transplant OS was 11.8 months (5.9, not evaluable) with 2-year survival probability (95% CI) of 46% (35% to 56%); some patients relapsed and needed additional treatment before HSCT (nâ¯=â¯28). Those who went directly to first HSCT upon remission with no additional salvage/induction treatment (nâ¯=â¯73) fared best: median post-transplant OS was not reached with a 2-year survival probability (95% CI) of 51% (39% to 62%). In patients with R/R ALL, InO followed by allogeneic HSCT provided an optimal long-term survival benefit among those with no previous HSCT who went directly to transplant after remission.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Inotuzumab Ozogamicina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Taxa de SobrevidaRESUMO
The Hedgehog (Hh) signaling pathway is activated in many cancers and is a promising target for therapeutic development. Deletions in the receptor Patched (PTCH) or activating mutations in Smoothened (SMO) have been reported in basal cell carcinoma and medulloblastoma, but are largely absent in most tumor types. Therefore, the mechanism of pathway activation in most cancers, including hematological malignancies, remains unknown. In normal tissues, Hh pathway activation via PTCH/SMO causes an increase in the downstream transcriptional activator GLI1 and a decrease in the GLI3 transcriptional repressor (GLI3R). In this article, we confirm that the Hh pathway is active in acute myeloid leukemia (AML), however, this activity is largely independent of SMO. Epigenetic and gene expression analysis of The Cancer Genome Atlas AML data set reveals that GLI3 expression is silenced in most AML patient samples, and the GLI3 locus is abnormally methylated. We show that GLI3R is required for the therapeutic effect of SMO antagonists in AML samples and restoration of GLI3R suppresses the growth of AML. We additionally demonstrate that GLI3R represses AML growth by downregulating AKT expression. In summary, this study provides the first evidence that GLI3R plays an essential role in SMO-independent Hh signaling in AML, and suggests that GLI3R could serve as a potential biomarker for patient selection in SMO antagonist clinical trials. Furthermore, these data support rational combinations of hypomethylating agents with SMO antagonists in clinical trials.
Assuntos
Proteínas Hedgehog/metabolismo , Fatores de Transcrição Kruppel-Like/fisiologia , Leucemia Mieloide Aguda/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteínas Repressoras/fisiologia , Receptor Smoothened/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Camundongos , Proteína Oncogênica v-akt/metabolismo , Proteína Gli3 com Dedos de ZincoRESUMO
Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Trial registration number: ClinicalTrials.gov identifier: NCT03416179.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos Clínicos , Leucemia Mieloide Aguda/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Masculino , Compostos de Fenilureia/administração & dosagem , Projetos de PesquisaRESUMO
BACKGROUND: Social networks such as Twitter offer the clinical research community a novel opportunity for engaging potential study participants based on user activity data. However, the availability of public social media data has led to new ethical challenges about respecting user privacy and the appropriateness of monitoring social media for clinical trial recruitment. Researchers have voiced the need for involving users' perspectives in the development of ethical norms and regulations. OBJECTIVE: This study examined the attitudes and level of concern among Twitter users and nonusers about using Twitter for monitoring social media users and their conversations to recruit potential clinical trial participants. METHODS: We used two online methods for recruiting study participants: the open survey was (1) advertised on Twitter between May 23 and June 8, 2017, and (2) deployed on TurkPrime, a crowdsourcing data acquisition platform, between May 23 and June 8, 2017. Eligible participants were adults, 18 years of age or older, who lived in the United States. People with and without Twitter accounts were included in the study. RESULTS: While nearly half the respondents-on Twitter (94/603, 15.6%) and on TurkPrime (509/603, 84.4%)-indicated agreement that social media monitoring constitutes a form of eavesdropping that invades their privacy, over one-third disagreed and nearly 1 in 5 had no opinion. A chi-square test revealed a positive relationship between respondents' general privacy concern and their average concern about Internet research (P<.005). We found associations between respondents' Twitter literacy and their concerns about the ability for researchers to monitor their Twitter activity for clinical trial recruitment (P=.001) and whether they consider Twitter monitoring for clinical trial recruitment as eavesdropping (P<.001) and an invasion of privacy (P=.003). As Twitter literacy increased, so did people's concerns about researchers monitoring Twitter activity. Our data support the previously suggested use of the nonexceptionalist methodology for assessing social media in research, insofar as social media-based recruitment does not need to be considered exceptional and, for most, it is considered preferable to traditional in-person interventions at physical clinics. The expressed attitudes were highly contextual, depending on factors such as the type of disease or health topic (eg, HIV/AIDS vs obesity vs smoking), the entity or person monitoring users on Twitter, and the monitored information. CONCLUSIONS: The data and findings from this study contribute to the critical dialogue with the public about the use of social media in clinical research. The findings suggest that most users do not think that monitoring Twitter for clinical trial recruitment constitutes inappropriate surveillance or a violation of privacy. However, researchers should remain mindful that some participants might find social media monitoring problematic when connected with certain conditions or health topics. Further research should isolate factors that influence the level of concern among social media users across platforms and populations and inform the development of more clear and consistent guidelines.
Assuntos
Comunicação , Mídias Sociais/estatística & dados numéricos , Rede Social , Ensaios Clínicos como Assunto , Humanos , Inquéritos e QuestionáriosRESUMO
Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9-48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4-19.3) months, with 12-month survival probability 66.6% (80% CI 58.5-73.4). The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia de Consolidação/métodos , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Quimioterapia de Manutenção/métodos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Indução de Remissão/métodos , Resultado do TratamentoRESUMO
The BCR-ABL1 fusion gene is caused by a translocation between chromosomes 9 and 22, resulting in an abnormal chromosome 22 (Philadelphia chromosome; Ph). Prior to the introduction of tyrosine kinase inhibitors (TKI), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukaemia (ALL). We compared the survival of Ph+ and Ph-ALL during the period when TKIs were universally available in the US for Ph+ALL, using a Surveillance, Epidemiology, and End Results (SEER) Database analysis. A total of 2694 patients with pre-B ALL (206 Ph+ALL; 2488 Ph-ALL) aged ≥18 years, who were diagnosed between 2010 and 2014, were identified in SEER registries. The median overall survival (OS) was 32 months in Ph+ALL (95% confidence interval [CI] 18 months-not reached) and 27 months (95% CI 24-30 months) in Ph-ALL (Log-rank test P-value 0·34). Older age was associated with worse prognosis in both Ph+ALL and Ph-ALL. Age-adjusted OS was inferior in Hispanics and African-Americans compared to non-Hispanic whites. Survival of pre-B ALL shows continued improvement with time. Philadelphia chromosome status does not confer poor prognosis in pre-B ALL in the TKI era: prognostic factors in pre-B ALL should be re-evaluated in the light of this finding.
Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Etnicidade , Humanos , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Proteínas Tirosina Quinases/antagonistas & inibidores , Sistema de Registros , Análise de Sobrevida , Adulto JovemRESUMO
Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplant are directed against the B-cell antigen cluster of differentiation 19 (CD19). The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. Although CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression-which may not be detectable using current routine methodologies-have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies for CD19-directed therapy is hampered by the exclusion of patients who have received prior CD19-directed therapies from major clinical trials. Antigen escape, which is attributed to mechanisms including epitope loss and defective cell surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy, and retrospective analyses indicate that some patients with disease relapse after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T has been limited to small case series. Prospective studies and detailed analyses are needed to understand how pretreatment and posttreatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy to fully maximize treatment strategies.
Assuntos
Antígenos CD19 , Linfoma Difuso de Grandes Células B , Humanos , Antígenos CD19/imunologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/genética , Imunoterapia Adotiva/métodos , Gerenciamento ClínicoRESUMO
High-grade serous ovarian carcinoma (HGSOC), the deadliest form of ovarian cancer, is typically diagnosed after it has metastasized and often relapses after standard-of-care platinum-based chemotherapy, likely due to advanced tumor stage, heterogeneity, and immune evasion and tumor-promoting signaling from the tumor microenvironment. To understand how spatial heterogeneity contributes to HGSOC progression and early relapse, we profiled an HGSOC tissue microarray of patient-matched longitudinal samples from 42 patients. We found spatial patterns associated with early relapse, including changes in T cell localization, malformed tertiary lymphoid structure (TLS)-like aggregates, and increased podoplanin-positive cancer-associated fibroblasts (CAFs). Using spatial features to compartmentalize the tissue, we found that plasma cells distribute in two different compartments associated with TLS-like aggregates and CAFs, and these distinct microenvironments may account for the conflicting reports about the role of plasma cells in HGSOC prognosis.
Assuntos
Antineoplásicos , Fibroblastos Associados a Câncer , Neoplasias Ovarianas , Feminino , Humanos , Fibroblastos Associados a Câncer/patologia , Recidiva Local de Neoplasia , Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Recidiva , Microambiente TumoralRESUMO
The most common subtype of lymphoma globally, diffuse large B cell lymphoma (DLBCL), is a leading cause of cancer death in people with HIV. The restructuring of the T cell compartment because of HIV infection and antiretroviral therapy (ART) may have implications for modern treatment selection, but current understanding of these dynamic interactions is limited. Here, we investigated the T cell response to DLBCL by sequencing the T cell receptor (TCR) repertoire in a cohort of HIV-negative (HIV-), HIV+/ART-experienced, and HIV+/ART-naive patients with DLBCL. HIV+/ART-naive tumor TCR repertoires were more clonal and more distinct from each other than HIV- and HIV+/ART-experienced ones. Further, increased overlap between tumor and blood TCR repertoires was associated with improved survival and HIV/ART status. Our study describes TCR repertoire characteristics for the first time to our knowledge in an African DLBCL cohort and demonstrates contributions of HIV infection and ART exposure to the DLBCL TCR repertoire.
Assuntos
Infecções por HIV , Linfoma Difuso de Grandes Células B , Receptores de Antígenos de Linfócitos T , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/virologia , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Masculino , Receptores de Antígenos de Linfócitos T/metabolismo , Feminino , Pessoa de Meia-Idade , Adulto , Linfócitos T/imunologia , Antirretrovirais/uso terapêuticoRESUMO
Immune checkpoints (CTLA4 & PD-1) are inhibitory pathways that block aberrant immune activity and maintain self-tolerance. Tumors co-opt these checkpoints to avoid immune destruction. Immune checkpoint inhibitors (ICIs) activate immune cells and restore their tumoricidal potential, making them highly efficacious cancer therapies. However, immunotolerant organs such as the liver depend on these tolerogenic mechanisms, and their disruption with ICI use can trigger the unintended side effect of hepatotoxicity termed immune-mediated liver injury from ICIs (ILICI). Learning how to uncouple ILICI from ICI anti-tumor activity is of paramount clinical importance. We developed a murine model to recapitulate human ILICI using CTLA4+/- mice treated with either combined anti-CTLA4 + anti-PDL1 or IgG1 + IgG2. We tested two forms of antisense oligonucleotides to knockdown caspase-3 in a total liver (parenchymal and non-parenchymal cells) or in a hepatocyte-specific manner. We also employed imaging mass cytometry (IMC), a powerful multiplex modality for immunophenotyping and cell interaction analysis in our model. ICI-treated mice had significant evidence of liver injury. We detected cleaved caspase-3 (cC3), indicating apoptosis was occurring, as well as Nod-like receptor protein 3 (NLRP3) inflammasome activation, but no necroptosis. Total liver knockdown of caspase-3 worsened liver injury, and induced further inflammasome activation, and Gasdermin-D-mediated pyroptosis. Hepatocyte-specific knockdown of caspase-3 reduced liver injury and NLRP3 inflammasome activation. IMC-generated single-cell data for 77,692 cells was used to identify 22 unique phenotypic clusters. Spatial analysis revealed that cC3+ hepatocytes had significantly closer interactions with macrophages, Kupffer cells, and NLRP3hi myeloid cells than other cell types. We also observed zones of three-way interaction between cC3+ hepatocytes, CD8 + T-cells, and macrophages. Our work is the first to identify hepatocyte apoptosis and NLRP3 inflammasome activation as drivers of ILICI. Furthermore, we report that the interplay between adaptive and innate immune cells is critical to hepatocyte apoptosis and ILICI.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Humanos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Antígeno CTLA-4/metabolismo , Caspase 3/metabolismo , Fígado/metabolismo , Apoptose , Hepatócitos/metabolismo , Comunicação CelularRESUMO
PURPOSE: About a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL. PATIENTS AND METHODS: We performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes. RESULTS: Highly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5+ Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay. CONCLUSION: We identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.
Assuntos
Doença de Hodgkin , Humanos , Doença de Hodgkin/tratamento farmacológico , Microambiente Tumoral , Ecossistema , Recidiva Local de Neoplasia , Resultado do Tratamento , RecidivaRESUMO
INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be spread by individuals unaware they are infected. Such dissemination has heightened ramifications in cancer patients, who may need to visit healthcare facilities frequently, be exposed to immune-compromising therapies, and face greater morbidity from coronavirus disease 2019 (COVID-19). We determined characteristics of (1) asymptomatic, clinically diagnosed, and (2) serologically documented but clinically undiagnosed SARS-CoV-2 infection among individuals with lung cancer. PATIENTS AND METHODS: In a multicenter registry, individuals with lung cancer (regardless of prior SARS-CoV-2 vaccination or documented infection) underwent collection of clinical data and serial blood samples, which were tested for antinucleocapsid protein antibody (anti-N Ab) or IgG (N) levels. We used multivariable logistic regression models to investigate clinical characteristics associated with the presence or absence of symptoms and the presence or absence of a clinical diagnosis among patients with their first SARS-CoV-2 infection. RESULTS: Among patients with serologic evidence or clinically documented SARS-CoV-2 infection, 80/142 (56%) had no reported symptoms at their first infection, and 61/149 (40%) were never diagnosed. Asymptomatic infection was more common among older individuals and earlier-stage lung cancer. In multivariable analysis, non-white individuals with SARS-CoV-2 serologic positivity were 70% less likely ever to be clinically diagnosed (P = .002). CONCLUSIONS: In a multicenter lung cancer population, a substantial proportion of SARS-CoV-2 infections had no associated symptoms or were never clinically diagnosed. Because such cases appear to occur more frequently in populations that may face greater COVID-19-associated morbidity, measures to limit disease spread and severity remain critical.
RESUMO
Several studies have found that high levels of reactive oxidative species (ROS) are associated with stem cell dysfunction. In the present study, we investigated the role of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of the antioxidant response, and found that it is required for hematopoietic stem progenitor cell (HSPC) survival and myeloid development. Although the loss of Nrf2 leads to increased ROS in most tissues, basal ROS levels in Nrf2-deficient (Nrf2(-/-)) BM were not elevated compared with wild-type. Nrf2(-/-) HSPCs, however, had increased rates of spontaneous apoptosis and showed decreased survival when exposed to oxidative stress. Nrf2(-/-) BM demonstrated defective stem cell function, as evidenced by reduced chimerism after transplantation that was not rescued by treatment with the antioxidant N-acetyl cysteine. Gene-expression profiling revealed that the levels of prosurvival cytokines were reduced in Nrf2(-/-) HSPCs. Treatment with the cytokine G-CSF improved HSPC survival after exposure to oxidative stress and rescued the transplantation defect in Nrf2(-/-) cells despite increases in ROS induced by cytokine signaling. These findings demonstrate a critical role for Nrf2 in hematopoiesis and stem cell survival that is independent of ROS levels.