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1.
Blood ; 142(26): 2282-2295, 2023 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-37774374

RESUMEN

ABSTRACT: The spatial anatomy of hematopoiesis in the bone marrow (BM) has been extensively studied in mice and other preclinical models, but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain thousands of paraffinized BM core biopsy tissue specimens, providing a rich resource for studying the intact human BM topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single-cell resolution, and artificial intelligence-based digital whole slide image analysis and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging. Our data indicate heterogeneity in marrow adipose tissue (MAT) content within each age group and an inverse correlation between MAT content and proportions of early myeloid and erythroid precursors, irrespective of age. We identify consistent endosteal and perivascular positioning of hematopoietic stem and progenitor cells (HSPCs) with medullary localization of more differentiated elements and, importantly, uncover new evidence of aging-associated changes in cellular and vascular morphologies, microarchitectural alterations suggestive of foci with increased lymphocytes, and diminution of a potentially active megakaryocytic niche. Overall, our findings suggest that there is topographic remodeling of human hematopoiesis associated with aging. More generally, we demonstrate the potential to deeply unravel the spatial biology of normal and pathologic human BM states using intact archival tissue specimens.


Asunto(s)
Inteligencia Artificial , Células Madre Hematopoyéticas , Humanos , Ratones , Animales , Células Madre Hematopoyéticas/patología , Médula Ósea/patología , Hematopoyesis/fisiología , Envejecimiento
3.
bioRxiv ; 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38328071

RESUMEN

Most diffuse large B-cell lymphoma (DLBCL) patients treated with bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was employed to characterize DLBCL immune environments, which effectively segregated DLBCLs into four quadrants - termed DLBCL-immune quadrants (IQ) - defined by cell-of-origin and immune-related gene set expression scores. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute to orchestrating unique DLBCL immune environments. In relapsed/refractory DLBCL patients, DLBCL-IQ assignment correlated significantly with clinical benefit with the CD20 x CD3 BsAb, mosunetuzumab, but not with CD19-directed CAR T cells. DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and uncovers the differential impact of the endogenous immune environment on outcomes to BsAb and CAR T cell treatment.

4.
Cancer Cell ; 42(3): 444-463.e10, 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38428410

RESUMEN

Follicular lymphoma (FL) is a generally incurable malignancy that evolves from developmentally blocked germinal center (GC) B cells. To promote survival and immune escape, tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment. Dynamic interactions between tumor B cells and the tumor microenvironment (TME) are hypothesized to contribute to the broad spectrum of clinical behaviors observed among FL patients. Despite the urgent need, existing clinical tools do not reliably predict disease behavior. Using a multi-modal strategy, we examined cell-intrinsic and -extrinsic factors governing progression and therapeutic outcomes in FL patients enrolled onto a prospective clinical trial. By leveraging the strengths of each platform, we identify several tumor-specific features and microenvironmental patterns enriched in individuals who experience early relapse, the most high-risk FL patients. These features include stromal desmoplasia and changes to the follicular growth pattern present 20 months before first progression and first relapse.


Asunto(s)
Linfoma Folicular , Humanos , Linfocitos B , Linfoma Folicular/genética , Multiómica , Estudios Prospectivos , Recurrencia , Microambiente Tumoral , Ensayos Clínicos como Asunto
5.
Nat Med ; 30(9): 2517-2527, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38886623

RESUMEN

PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Depsipéptidos , Linfoma de Células T , Humanos , Depsipéptidos/efectos adversos , Depsipéptidos/uso terapéutico , Depsipéptidos/administración & dosificación , Persona de Mediana Edad , Femenino , Masculino , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/efectos adversos , Anciano de 80 o más Años , Dosis Máxima Tolerada , Isoquinolinas , Purinas
6.
J Immunother Cancer ; 11(6)2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37364933

RESUMEN

BACKGROUND: PD-1 checkpoint blockade therapy (CBT) has greatly benefited patients with select solid tumors and lymphomas but has limited efficacy against diffuse large B-cell lymphoma (DLBCL). Because numerous inhibitory checkpoint receptors have been implicated in driving tumor-specific T cell dysfunction, we hypothesized that combinatorial CBT would enhance the activity of anti-PD-1-based therapy in DLBCL. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a coinhibitory receptor expressed on dysfunctional tumor-infiltrating T cells, and TIGIT blockade has demonstrated encouraging activity in combination with PD-1 blockade in murine tumor models and in clinical studies. However, the degree to which TIGIT mediates T cell dysfunction in DLBCL has not been fully explored. RESULTS: Here, we demonstrate that TIGIT is broadly expressed on lymphoma-infiltrating T cells (LITs) across a variety of human lymphomas and is frequently coexpressed with PD-1. TIGIT expression is particularly common on LITs in DLBCL, where TIGIT+ LITs often form distinct cellular communities and exhibit significant contact with malignant B cells. TIGIT+/PD-1+ LITs from human DLBCL and murine lymphomas exhibit hypofunctional cytokine production on ex vivo restimulation. In mice with established, syngeneic A20 B-cell lymphomas, TIGIT or PD-1 mono-blockade leads to modest delays in tumor outgrowth, whereas PD-1 and TIGIT co-blockade results in complete rejection of A20 lymphomas in most mice and significantly prolongs survival compared with mice treated with monoblockade therapy. CONCLUSIONS: These results provide rationale for clinical investigation of TIGIT and PD-1 blockade in lymphomas, including DLBCL.


Asunto(s)
Linfoma de Células B Grandes Difuso , Receptor de Muerte Celular Programada 1 , Humanos , Animales , Ratones , Receptores Inmunológicos/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología
7.
Cell Rep ; 40(7): 111180, 2022 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-35977503

RESUMEN

Intratumor heterogeneity (ITH) represents a major challenge for anticancer therapies. An integrated, multidimensional, multiregional approach dissecting ITH of the clear cell renal cell carcinoma (ccRCC) tumor microenvironment (TME) is employed at the single-cell level with mass cytometry (CyTOF), multiplex immunofluorescence (MxIF), and single-nucleus RNA sequencing (snRNA-seq) and at the bulk level with whole-exome sequencing (WES), RNA-seq, and methylation profiling. Multiregional analyses reveal unexpected conservation of immune composition within each individual patient, with profound differences among patients, presenting patient-specific tumor immune microenvironment signatures despite underlying genetic heterogeneity from clonal evolution. Spatial proteogenomic TME analysis using MxIF identifies 14 distinct cellular neighborhoods and, conversely, demonstrated architectural heterogeneity among different tumor regions. Tumor-expressed cytokines are identified as key determinants of the TME and correlate with clinical outcome. Overall, this work signifies that spatial ITH occurs in ccRCC, which may drive clinical heterogeneity and warrants further interrogation to improve patient outcomes.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Proteogenómica , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Citocinas/genética , Heterogeneidad Genética , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Análisis de la Célula Individual , Microambiente Tumoral/genética
8.
Clin Genitourin Cancer ; 19(6): e374-e381, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34389275

RESUMEN

BACKGROUND: Although there are immune checkpoint inhibitors (ICIs) available for the treatment of renal cell carcinoma (RCC), the utility of PD-L1 detection by immunohistochemistry (IHC) as a predictive biomarker in clear cell RCC (ccRCC) remains controversial. Nevertheless, alternative methods for PD-L1 detection, such as RNA sequencing (RNA-Seq), may be clinically useful in ccRCC; therefore, we sought to determine the ability of RNA-Seq to accurately and sensitively detect PD-L1 expression across different ccRCC clinical samples in comparison with IHC. PATIENTS AND METHODS: Patients with ccRCC (n=127) who received treatment from Washington University in St. Louis between 2018 and 2020 were identified. Tumors from these patients were analyzed using RNA-Seq and IHC. RESULTS: PD-L1 detection by RNA-Seq strongly correlated with IHC (P < .001), which was further validated using two independent datasets. Furthermore, RNA-Seq analysis identified an immune-enriched (higher PD-L1 positivity) and an immune-desert (lower PD-L1 positivity) microenvironment of ccRCC, which also correlated with IHC (P < .00001). CONCLUSION: The results demonstrate the ability of RNA-Seq to detect PD-L1 in various ccRCC clinical samples compared to IHC. Ultimately, these findings suggest that PD-L1 detection by RNA-Seq can be further developed to determine the clinical utility of this methodology in ccRCC.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Antígeno B7-H1/genética , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Humanos , Inmunohistoquímica , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , RNA-Seq , Microambiente Tumoral
9.
Clin Cancer Res ; 27(12): 3478-3490, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33771855

RESUMEN

PURPOSE: Multiparametric MRI (mpMRI) has become an indispensable radiographic tool in diagnosing prostate cancer. However, mpMRI fails to visualize approximately 15% of clinically significant prostate cancer (csPCa). The molecular, cellular, and spatial underpinnings of such radiographic heterogeneity in csPCa are unclear. EXPERIMENTAL DESIGN: We examined tumor tissues from clinically matched patients with mpMRI-invisible and mpMRI-visible csPCa who underwent radical prostatectomy. Multiplex immunofluorescence single-cell spatial imaging and gene expression profiling were performed. Artificial intelligence-based analytic algorithms were developed to examine the tumor ecosystem and integrate with corresponding transcriptomics. RESULTS: More complex and compact epithelial tumor architectures were found in mpMRI-visible than in mpMRI-invisible prostate cancer tumors. In contrast, similar stromal patterns were detected between mpMRI-invisible prostate cancer and normal prostate tissues. Furthermore, quantification of immune cell composition and tumor-immune interactions demonstrated a lack of immune cell infiltration in the malignant but not in the adjacent nonmalignant tissue compartments, irrespective of mpMRI visibility. No significant difference in immune profiles was detected between mpMRI-visible and mpMRI-invisible prostate cancer within our patient cohort, whereas expression profiling identified a 24-gene stromal signature enriched in mpMRI-invisible prostate cancer. Prostate cancer with strong stromal signature exhibited a favorable survival outcome within The Cancer Genome Atlas prostate cancer cohort. Notably, five recurrences in the 8 mpMRI-visible patients with csPCa and no recurrence in the 8 clinically matched patients with mpMRI-invisible csPCa occurred during the 5-year follow-up post-prostatectomy. CONCLUSIONS: Our study identified distinct molecular, cellular, and structural characteristics associated with mpMRI-visible csPCa, whereas mpMRI-invisible tumors were similar to normal prostate tissue, likely contributing to mpMRI invisibility.


Asunto(s)
Imágenes de Resonancia Magnética Multiparamétrica , Neoplasias de la Próstata , Inteligencia Artificial , Ecosistema , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Proteómica
10.
Blood Cancer J ; 11(7): 130, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34267181

RESUMEN

Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Cells in the microenvironment may be a key contributor to treatment failure. We used a discovery and validation study design to identify microenvironmental determinants of early failure and then integrated these results into the FLIPI. In total, 496 newly diagnosed FL grade 1-3 A patients who were prospectively enrolled into the MER cohort from 2002 to 2012 were evaluated. Tissue microarrays were stained for CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRP-α, TIM3, PD-1, and PD-L1. Early failure was defined as failing to achieve event-free survival at 24 months (EFS24) in immunochemotherapy-treated patients and EFS12 in all others. CyTOF and CODEX analysis were performed to characterize intratumoral immunophenotypes. Lack of intrafollicular CD4 expression was the only predictor of early failure that replicated with a pooled OR 2.37 (95%CI 1.48-3.79). We next developed a bio-clinical risk model (BioFLIPI), where lack of CD4 intrafollicular expression moved patients up one FLIPI risk group, adding a new fourth high-risk group. Compared with BioFLIPI score of 1, patients with a score of 2 (OR 2.17; 95% CI 1.08-4.69), 3 (OR 3.53; 95% CI 1.78-7.54), and 4 (OR 8.92; 95% CI 4.00-21.1) had increasing risk of early failure. The favorable intrafollicular CD4 T cells were identified as activated central memory T cells, whose prognostic value was independent from genetic features. In conclusion, lack of intrafollicular CD4 expression predicts early failure in FL and combined with FLIPI improves identification of high-risk patients; however, independent validation is warranted.


Asunto(s)
Antígenos CD4/análisis , Linfoma Folicular/diagnóstico , Células T de Memoria/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD4/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patología , Masculino , Células T de Memoria/metabolismo , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Microambiente Tumoral , Adulto Joven
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