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1.
Sci Adv ; 10(44): eadq6830, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39475596

RESUMEN

Despite immunotherapy's promise in cancer treatment, patient responses vary substantially because of the individual nature of the immune system and the lack of reliable biomarkers. To address this issue, we developed a precision ex vivo platform that integrates patient-specific tumor and immune cells to study the mechanisms of antitumor immune response, predict immunotherapy outcomes, and identify effective treatments. This platform revealed unique single-cell immune response mechanisms and sensitivities to standard-of-care immunotherapies. Furthermore, we were able to identify a synergistic combination of anti-programmed cell death protein 1 (anti-PD-1) together with a Casitas B lineage lymphoma-b inhibitor that overcame anti-PD-1 resistance in selected patient samples. Activation of the interferon-γ-stimulated cytokines predicted combination efficacy, while immunosuppressive cytokines were associated with poor response. Our findings underscore the platform's potential in tailoring immunotherapies and advancing drug development, offering avenues for personalized cancer treatment.


Asunto(s)
Inmunoterapia , Neoplasias Pulmonares , Medicina de Precisión , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Medicina de Precisión/métodos , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Citocinas/metabolismo
2.
Blood ; 144(15): 1595-1610, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-38941598

RESUMEN

ABSTRACT: T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, that is, the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (1) altered epigenetics, (2) defective DNA damage responses, (3) aberrant cell-cycle regulation, and (4) deregulated prosurvival pathways, including T-cell receptor and JAK/STAT signaling. To further develop related preclinical therapeutic concepts, we studied inhibitors of histone deacetylases ([H]DACs), B-cell lymphoma 2 (BCL2), cyclin-dependent kinase (CDK), mouse double minute 2 (MDM2), and classical cytostatics, using (1) single-agent and combinatorial compound testing in 20 well-characterized and molecularly profiled primary T-PLL (validated by additional 42 cases) and (2) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single agents and combinations (in vitro and in mice) included cladribine, romidepsin ([H]DAC), venetoclax (BCL2), and/or idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance toward MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activation and downstream signals (including enhanced accessibility of target-gene chromatin regions), in particular synergy with insults by cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.


Asunto(s)
Apoptosis , Daño del ADN , Leucemia Prolinfocítica de Células T , Proteína p53 Supresora de Tumor , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Apoptosis/efectos de los fármacos , Humanos , Daño del ADN/efectos de los fármacos , Animales , Ratones , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/patología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Sulfonamidas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores
3.
Sci Adv ; 10(23): eadj0787, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38848368

RESUMEN

Somatic mutations in T cells can cause cancer but also have implications for immunological diseases and cell therapies. The mutation spectrum in nonmalignant T cells is unclear. Here, we examined somatic mutations in CD4+ and CD8+ T cells from 90 patients with hematological and immunological disorders and used T cell receptor (TCR) and single-cell sequencing to link mutations with T cell expansions and phenotypes. CD8+ cells had a higher mutation burden than CD4+ cells. Notably, the biggest variant allele frequency (VAF) of non-synonymous variants was higher than synonymous variants in CD8+ T cells, indicating non-random occurrence. The non-synonymous VAF in CD8+ T cells strongly correlated with the TCR frequency, but not age. We identified mutations in pathways essential for T cell function and often affected lymphoid neoplasia. Single-cell sequencing revealed cytotoxic TEMRA phenotypes of mutated T cells. Our findings suggest that somatic mutations contribute to CD8+ T cell expansions without malignant transformation.


Asunto(s)
Linfocitos T CD8-positivos , Mutación , Receptores de Antígenos de Linfocitos T , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Adulto , Análisis de la Célula Individual , Masculino , Femenino , Persona de Mediana Edad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Frecuencia de los Genes , Fenotipo , Anciano
4.
J Immunother Cancer ; 12(4)2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38604809

RESUMEN

BACKGROUND: Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level. METHODS: Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity. RESULTS: We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity. CONCLUSIONS: Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Compuestos Bicíclicos Heterocíclicos con Puentes , Metformina , Sulfonamidas , Humanos , Femenino , Complejo I de Transporte de Electrón/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Células Dendríticas , Metformina/farmacología , Metformina/uso terapéutico , Microambiente Tumoral
5.
J Clin Invest ; 134(8)2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38618957

RESUMEN

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Animales , Humanos , Ratones , Ratones Transgénicos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Tirosina Quinasas , Receptores de Antígenos de Linfocitos T/genética , Transducción de Señal , Factor de Transcripción STAT5/genética
6.
Mol Med ; 30(1): 48, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38594612

RESUMEN

BACKGROUND: Immune-mediated arthritis is a group of autoinflammatory diseases, where the patient's own immune system attacks and destroys synovial joints. Sustained remission is not always achieved with available immunosuppressive treatments, warranting more detailed studies of T cell responses that perpetuate synovial inflammation in treatment-refractory patients. METHODS: In this study, we investigated CD4 + and CD8 + T lymphocytes from the synovial tissue and peripheral blood of patients with treatment-resistant immune-mediated arthritis using paired single-cell RNA and TCR-sequencing. To gain insights into the trafficking of clonal families, we compared the phenotypes of clones with the exact same TCRß amino acid sequence between the two tissues. RESULTS: Our results show that both CD4 + and CD8 + T cells display a more activated and inflamed phenotype in the synovial tissue compared to peripheral blood both at the population level and within individual T cell families. Furthermore, we found that both cell subtypes exhibited clonal expansion in the synovial tissue. CONCLUSIONS: Our findings suggest that the local environment in the synovium drives the proliferation of activated cytotoxic T cells, and both CD4 + and CD8 + T cells may contribute to tissue destruction and disease pathogenesis.


Asunto(s)
Artritis , Linfocitos T CD8-positivos , Humanos , Linfocitos T CD8-positivos/metabolismo , Artritis/metabolismo , Artritis/patología , Membrana Sinovial , Células Clonales , Secuencia de Aminoácidos , Linfocitos T CD4-Positivos/metabolismo
7.
Cell Rep Med ; 5(5): 101521, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38653245

RESUMEN

BCR::ABL1-independent pathways contribute to primary resistance to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) and play a role in leukemic stem cell persistence. Here, we perform ex vivo drug screening of CML CD34+ leukemic stem/progenitor cells using 100 single drugs and TKI-drug combinations and identify sensitivities to Wee1, MDM2, and BCL2 inhibitors. These agents effectively inhibit primitive CD34+CD38- CML cells and demonstrate potent synergies when combined with TKIs. Flow-cytometry-based drug screening identifies mepacrine to induce differentiation of CD34+CD38- cells. We employ genome-wide CRISPR-Cas9 screening for six drugs, and mediator complex, apoptosis, and erythroid-lineage-related genes are identified as key resistance hits for TKIs, whereas the Wee1 inhibitor AZD1775 and mepacrine exhibit distinct resistance profiles. KCTD5, a consistent TKI-resistance-conferring gene, is found to mediate TKI-induced BCR::ABL1 ubiquitination. In summary, we delineate potential mechanisms for primary TKI resistance and non-BCR::ABL1-targeting drugs, offering insights for optimizing CML treatment.


Asunto(s)
Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Sistemas CRISPR-Cas/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-abl/metabolismo , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Línea Celular Tumoral
8.
J Clin Oncol ; 42(16): 1875-1880, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38471049

RESUMEN

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The European Stop Kinase Inhibitors (EURO-SKI) study is the largest clinical trial for investigating the cessation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in stable deep molecular remission (DMR). Among 728 patients, 434 patients (61%; 95% CI, 57 to 64) remained in major molecular response (MMR) at 6 months and 309 patients of 678 (46%; 95% CI, 42 to 49) at 36 months. Duration of TKI treatment and DMR before TKI stop were confirmed as significant factors for the prediction of MMR loss at 6 months. In addition, the type of BCR::ABL1 transcript was identified as a prognostic factor. For late MMR losses after 6 months, TKI treatment duration, percentage of blasts in peripheral blood, and platelet count at diagnosis were significant factors in multivariate analysis. For the entire study period of 36 months, multiple logistic regression models confirmed duration of treatment, blasts, and transcript type as independent factors for MMR maintenance. In addition to the duration of treatment, transcript type as well as blasts in peripheral blood at diagnosis should be considered as important factors to predict treatment-free remission.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Inducción de Remisión , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Femenino , Persona de Mediana Edad , Masculino , Adulto , Anciano , Pronóstico , Mesilato de Imatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Europa (Continente) , Adulto Joven , Anciano de 80 o más Años , Resultado del Tratamiento
10.
Nat Commun ; 15(1): 1158, 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38326354

RESUMEN

Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods. However, transcriptional changes that drive cells into resistant fates may be subtle, necessitating high resolution analysis. Here, we present ReSisTrace that uses shared transcriptomic features of sister cells to predict the states priming treatment resistance. Applying ReSisTrace in ovarian cancer cells perturbed with olaparib, carboplatin or natural killer (NK) cells reveals pre-resistant phenotypes defined by proteostatic and mRNA surveillance features, reflecting traits enriched in the upcoming subclonal selection. Furthermore, we show that DNA repair deficiency renders cells susceptible to both DNA damaging agents and NK killing in a context-dependent manner. Finally, we leverage the obtained pre-resistance profiles to predict and validate small molecules driving cells to sensitive states prior to treatment. In summary, ReSisTrace resolves pre-existing transcriptional features of treatment vulnerability, facilitating both molecular patient stratification and discovery of synergistic pre-sensitizing therapies.


Asunto(s)
Células Asesinas Naturales , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/genética , Carboplatino , Fenotipo , Línea Celular Tumoral
11.
Clin Cancer Res ; 30(11): 2514-2530, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38252421

RESUMEN

PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.


Asunto(s)
Lectinas Tipo C , Receptores Inmunológicos , Animales , Humanos , Ratones , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Línea Celular Tumoral , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Lectinas Tipo C/metabolismo , Lectinas Tipo C/inmunología , Lectinas Tipo C/antagonistas & inhibidores , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Linfoma de Células T/terapia , Linfoma de Células T/tratamiento farmacológico , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Leukemia ; 38(4): 781-787, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38278960

RESUMEN

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Dasatinib/efectos adversos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inducción de Remisión , Resultado del Tratamiento
13.
Leukemia ; 38(1): 109-125, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37919606

RESUMEN

Immunological control of residual leukemia cells is thought to occur in patients with chronic myeloid leukemia (CML) that maintain treatment-free remission (TFR) following tyrosine kinase inhibitor (TKI) discontinuation. To study this, we analyzed 55 single-cell RNA and T cell receptor (TCR) sequenced samples (scRNA+TCRαß-seq) from patients with CML (n = 13, N = 25), other cancers (n = 28), and healthy (n = 7). The high number and active phenotype of natural killer (NK) cells in CML separated them from healthy and other cancers. Most NK cells in CML belonged to the active CD56dim cluster with high expression of GZMA/B, PRF1, CCL3/4, and IFNG, with interactions with leukemic cells via inhibitory LGALS9-TIM3 and PVR-TIGIT interactions. Accordingly, upregulation of LGALS9 was observed in CML target cells and TIM3 in NK cells when co-cultured together. Additionally, we created a classifier to identify TCRs targeting leukemia-associated antigen PR1 and quantified anti-PR1 T cells in 90 CML and 786 healthy TCRß-sequenced samples. Anti-PR1 T cells were more prevalent in CML, enriched in bone marrow samples, and enriched in the mature, cytotoxic CD8 + TEMRA cluster, especially in a patient maintaining TFR. Our results highlight the role of NK cells and anti-PR1 T cells in anti-leukemic immune responses in CML.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Receptor 2 Celular del Virus de la Hepatitis A , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Análisis de la Célula Individual
14.
Leukemia ; 38(2): 318-325, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38129513

RESUMEN

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.


Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/uso terapéutico , Pronóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas de Transporte de Membrana/uso terapéutico , Resultado del Tratamiento
15.
Immunity ; 56(12): 2816-2835.e13, 2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-38091953

RESUMEN

Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers. CRISPR screens in cancer cells uncovered genes regulating sensitivity and resistance to NK cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, and transcriptional regulators, in addition to confirming the importance of antigen presentation and death receptor signaling pathways. CRISPR screens with a single-cell transcriptomic readout provided insight into underlying mechanisms, including regulation of IFN-γ signaling in cancer cells and NK cell activation states. Our findings highlight the diversity of mechanisms influencing NK cell susceptibility across different cancers and provide a resource for NK cell-based therapies.


Asunto(s)
Neoplasias Hematológicas , Neoplasias , Humanos , Células Asesinas Naturales , Neoplasias/genética , Presentación de Antígeno , Genómica , Citotoxicidad Inmunológica/genética , Línea Celular Tumoral
16.
Bioinformatics ; 39(12)2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-38070156

RESUMEN

MOTIVATION: T cells play an essential role in adaptive immune system to fight pathogens and cancer but may also give rise to autoimmune diseases. The recognition of a peptide-MHC (pMHC) complex by a T cell receptor (TCR) is required to elicit an immune response. Many machine learning models have been developed to predict the binding, but generalizing predictions to pMHCs outside the training data remains challenging. RESULTS: We have developed a new machine learning model that utilizes information about the TCR from both α and ß chains, epitope sequence, and MHC. Our method uses ProtBERT embeddings for the amino acid sequences of both chains and the epitope, as well as convolution and multi-head attention architectures. We show the importance of each input feature as well as the benefit of including epitopes with only a few TCRs to the training data. We evaluate our model on existing databases and show that it compares favorably against other state-of-the-art models. AVAILABILITY AND IMPLEMENTATION: https://github.com/DaniTheOrange/EPIC-TRACE.


Asunto(s)
Receptores de Antígenos de Linfocitos T , Linfocitos T , Epítopos , Receptores de Antígenos de Linfocitos T/química , Secuencia de Aminoácidos , Linfocitos T/metabolismo , Unión Proteica , Epítopos de Linfocito T/metabolismo
17.
Cancer Res Commun ; 3(7): 1260-1276, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37484198

RESUMEN

The successful use of expanded tumor-infiltrating lymphocytes (TIL) in adoptive TIL therapies has been reported, but the effects of the TIL expansion, immunophenotype, function, and T cell receptor (TCR) repertoire of the infused products relative to the tumor microenvironment (TME) are not well understood. In this study, we analyzed the tumor samples (n = 58) from treatment-naïve patients with renal cell carcinoma (RCC), "pre-rapidly expanded" TILs (pre-REP TIL, n = 15) and "rapidly expanded" TILs (REP TIL, n = 25) according to a clinical-grade TIL production protocol, with single-cell RNA (scRNA)+TCRαß-seq (TCRαß sequencing), TCRß-sequencing (TCRß-seq), and flow cytometry. REP TILs encompassed a greater abundance of CD4+ than CD8+ T cells, with increased LAG-3 and low PD-1 expressions in both CD4+ and CD8+ T cell compartments compared with the pre-REP TIL and tumor T cells. The REP protocol preferentially expanded small clones of the CD4+ phenotype (CD4, IL7R, KLRB1) in the TME, indicating that the largest exhausted T cell clones in the tumor do not expand during the expansion protocol. In addition, by generating a catalog of RCC-associated TCR motifs from >1,000 scRNA+TCRαß-seq and TCRß-seq RCC, healthy and other cancer sample cohorts, we quantified the RCC-associated TCRs from the expansion protocol. Unlike the low-remaining amount of anti-viral TCRs throughout the expansion, the quantity of the RCC-associated TCRs was high in the tumors and pre-REP TILs but decreased in the REP TILs. Our results provide an in-depth understanding of the origin, phenotype, and TCR specificity of RCC TIL products, paving the way for a more rationalized production of TILs. Significance: TILs are a heterogenous group of immune cells that recognize and attack the tumor, thus are utilized in various clinical trials. In our study, we explored the TILs in patients with kidney cancer by expanding the TILs using a clinical-grade protocol, as well as observed their characteristics and ability to recognize the tumor using in-depth experimental and computational tools.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Linfocitos Infiltrantes de Tumor , Carcinoma de Células Renales/genética , Linfocitos T CD8-positivos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Microambiente Tumoral
18.
Br J Cancer ; 129(4): 683-695, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37391505

RESUMEN

BACKGROUND: Technical factors can bias H&E digital slides potentially compromising computational histopathology studies. Here, we hypothesised that sample quality and sampling variation can introduce even greater and undocumented technical fallacy. METHODS: Using The Cancer Genome Atlas (TCGA) clear-cell renal cell carcinoma (ccRCC) as a model disease, we annotated ~78,000 image tiles and trained deep learning models to detect histological textures and lymphocyte infiltration at the tumour core and its surrounding margin and correlated these with clinical, immunological, genomic, and transcriptomic profiles. RESULTS: The models reached 95% validation accuracy for classifying textures and 95% for lymphocyte infiltration enabling reliable profiling of ccRCC samples. We validated the lymphocyte-per-texture distributions in the Helsinki dataset (n = 64). Texture analysis indicated constitutive sampling bias by TCGA clinical centres and technically suboptimal samples. We demonstrate how computational texture mapping (CTM) can abrogate these issues by normalising textural variance. CTM-harmonised histopathological architecture resonated with both expected associations and novel molecular fingerprints. For instance, tumour fibrosis associated with histological grade, epithelial-to-mesenchymal transition, low mutation burden and metastasis. CONCLUSIONS: This study highlights texture-based standardisation to resolve technical bias in computational histopathology and understand the molecular basis of tissue architecture. All code, data and models are released as a community resource.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología
19.
Haematologica ; 108(10): 2626-2638, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37078252

RESUMEN

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.


Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Proteína bcl-X/genética , Proteínas Proto-Oncogénicas c-bcl-2 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Senescencia Celular , Línea Celular Tumoral , Apoptosis
20.
Blood ; 142(1): 73-89, 2023 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-37018663

RESUMEN

Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.


Asunto(s)
Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva , Animales , Ratones , Médula Ósea/metabolismo , Quimiocinas CXC/metabolismo , Quimiocinas CXC/farmacología , Quimiocinas CXC/uso terapéutico , Citocinas/metabolismo , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Células Madre Neoplásicas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal
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