Experimental Hematology & Oncology最新文献

Background: SPP1 + macrophages are among the major phagocytic cells, yet promoting tumor immune evasion and predicting unfavorable prognosis, in various cancer types. Meanwhile, the predictive value of the abundance of SPP1 + macrophages in patients receiving immunotherapy remains debatable, indicating the potential existence of subtypes of SPP1 + macrophages with diverse biological functions.

Methods: The single cell RNA sequencing data of myeloid cells integrated from several cancers including esophageal squamous cell carcinoma was analyzed for characterizing the function and cellular interactions of SPP1 + macrophages expressing SIRPα. Multiplexed immunohistochemistry was used to quantify the quantity and spatial distribution of SPP1 + macrophages expressing SIRPα. Kaplan-Meier method was used for survival analysis. In vitro and in vivo studies investigating the function of SPP1 + macrophages were performed.

Results: SPP1 + macrophages possessed a high phagocytic signature and could engulf more tumor cells in vitro and in vivo. SIRPα expression could represent the phagocytic activity of SPP1 + macrophages and delineated subsets of SPP1 + macrophages with different functions. SPP1 + SIRPα + macrophages showed close spatial distance to tumor cells and positively correlated with PD1 + CD8 + T cells. A high abundance of SPP1 + SIRPα + macrophages at baseline corresponded to patients' response to PD-1/PD-L1 inhibitors.

Conclusion: A novel subtype of SPP1 + macrophages expressing SIRPα was identified and their abundance predicted patients' response to PD-1/PD-L1 inhibitors.

Background: A tyrosine kinase inhibitor (TKI) such as Imatinib (IM) is the preferred treatment for Chronic Myeloid Leukemia (CML). However, the emergence of IM resistance presents a significant challenge to disease management. A characteristic of cancer cells, including IM-resistant CMLs, are characterized by heightened uptake of glucose and aberrant glycolysis in the cytosol, which is known as the Warburg effect. In addition to its potential to modulate the Warburg effect, Chiglitazar (Chi), a compound that regulates glucose metabolism, has also been investigated for its implication in cancer treatment. This suggests that combining Chi with IM may be a therapeutic strategy for overcoming IM resistance in CML.

Methods: Sensitive and IM-resistance CML cells were treated with Chi in vitro, followed by detecting of extracellular acidification rate (ECAR) using a Seahorse XF Analyzer. CML cell proliferation, cell cycle distribution, and apoptosis were tested by CCK-8 assay and flow cytometry. RNA sequencing was utilized to investigate potential transcriptional changes induced by Chi usage. In vivo studies were conducted on immunodeficient mice implanted with CML cells and given Chi and/or IM later. Tumor growth was monitored, as well as tumor burden and survival rates between groups.

Results: Our metabonomic, transcriptomic, and molecular biology studies demonstrated that Chi, in part, diminished the Warburg effect by reducing glucose and lactate production in imatinib-resistant CML cells through the PPARγ/mTOR/PKM2 pathway. This modulation of glucose metabolism resulted in reduced cell proliferation and enhanced sensitivity to IM in imatinib-resistant CML cells in vitro. Rescue assay by introducing shPPARγ or mTOR activator verified the underlying regulatory pathway. Also, the combination of Chi and IM synergistically increased the sensitivity of IM in vivo and prolonged the survival of imatinib-resistance CML transplanted mice.

Conclusions: Our results demonstrated the potential of Chi to overcome IM resistance in vitro and in vivo. By inhibiting the Warburg effect through the PPARγ/mTOR/PKM2 pathway, Chi resensitizes CML cells towards imatinib treatment. Combining IM with Chi is an alternative therapeutic option for CML management, especially for IM-resistant CML patients.

Radiotherapy is widely used as an effective non-surgical strategy to control malignant tumors. However, recurrence is one of common causes of treatment failure even after the effective radiotherapy. In this study, we focused on the effects of radiation-induced exosomal miR-21 on the tumor microenvironment to investigate the causes of recurrence. Analysis of the TCGA database revealed that breast cancer patients with high levels of miR-21 have significantly reduced overall survival when treated with radiotherapy compared to those who did not receive radiotherapy, indicating a high hazard ratio for miR-21 in patients undergoing this treatment. Additionally, exosomal miR-21 is found to be highly expressed in the serum of breast adenocarcinoma patients. To explore how miR-21 induces poor prognosis in irradiated breast cancer, we irradiated 4T1 cell line with low or high doses of radiation, and examined the impact of secreted exosomal miR-21 on breast cancer cell and tumor microenvironment. After 10 Gy irradiation, 4T1 cells secreted 2.20 ± 0.10 times more exosomes and exhibited a 1.85 ± 0.01-fold increase in exosomal miR-21 levels. Treatment with exosomes from 10 Gy-irradiated cancer cells led to enhanced tumor cell proliferation, wound healing, and migration. The survival rate of 10 Gy-irradiated tumor cells incubated with 10 Gy-derived exosomes increased by 2.83-fold. Moreover, the growth of subcutaneous tumors treated with 10 Gy exosomes (n = 13) was significantly faster compared to tumors treated with 0 Gy exosomes (n = 10, P < 0.05). In summary, our study revealed high-dose irradiation-induced exosomes were found to enhance tumor proliferation and invasiveness via the transfer of exosomal miR-21. Based on these findings, we suggest that radiation-induced exosomal miR-21 may contribute to a poorer prognosis of breast cancer patients undergoing radiotherapy.

Immunotherapy has transformed the landscape of cancer treatment, with chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy emerging as a front runner in addressing some hematological malignancies. Despite its considerable efficacy, the occurrence of severe adverse effects associated with CAR-T cell therapy has limited their scope and prompted the exploration of alternative therapeutic strategies. Natural killer (NK) cells, characterized by both their innate cytotoxicity and ability to lyse target cells without the constraint of peptide specificity conferred by a major histocompatibility complex (MHC), have similarly garnered attention as a viable immunotherapy. As such, another therapeutic approach has recently emerged that seeks to combine the continued success of CAR-T cell therapy with the flexibility of NK cells. Clinical trials involving CAR-engineered NK (CAR-NK) cell therapy have exhibited promising efficacy with fewer deleterious side effects. This review aims to provide a concise overview of the cellular and molecular basis of NK cell biology, facilitating a better understanding of advancements in CAR design and manufacturing. The focus is on current approaches and strategies employed in CAR-NK cell development, exploring at both preclinical and clinical settings. We will reflect upon the achievements, advantages, and challenges intrinsic to CAR-NK cell therapy. Anticipating the maturation of CAR-NK cell therapy technology, we foresee its encouraging prospects for a broader range of cancer patients and other conditions. It is our belief that this CAR-NK progress will bring us closer to making significant strides in the treatment of refractory and recurrent cancers, as well as other immune-mediated disorders.

Relapsed/refractory T cell-derived malignancies present with high heterogeneity and poor prognoses. Recently, chimeric antigen receptor (CAR)-T cell therapy has shown remarkable safety and efficacy in the treatment of B cell-derived malignancies. However, the treatment of CAR-T cells in T cell-derived malignancies has more limitations, such as fratricide, T cell aplasia, and tumor contamination, mainly because of the similarity between normal and malignant T cells. Pan-T antigen CAR-T cells (such as CD5 and CD7 targets), the most widely used CAR-T cells in clinical trials, can cover almost all T cell-derived malignant cells but can also induce severe killing of CAR-T cells and normal T cells. Compared to autologous sources of CAR-T cells, allogeneic CAR-T cells can prevent tumor contamination and become universal products by gene-editing. However, none of these CAR-T cells could completely prevent immune deficiency and disease relapse after T-targeted CAR-T cell therapy. In this review, we summarize the current challenges of CAR-T cell therapy for T cell-derived malignancies in clinical practice and potential strategies to address these limitations.

Multiple myeloma (MM) is an incurable disease characterized by the abnormal expansion of plasma cells in the bone marrow (BM). Numerous studies have shown that BM tumor cells can influence the tumor microenvironment (TME) through communication with extracellular vesicle circular RNAs (circRNAs), a type of noncoding RNA. Our study revealed that a circular RNA, circRFWD2 (hsa_circ_0015361), is expressed by MM cells and translated into a new protein, circRFWD2_369aa. We found that elevated levels of circRFWD2_369aa in MM peripheral blood samples were closely associated with poor outcomes in MM patients. Further investigation revealed that circRFWD2 promoted the degradation of p27 through the ubiquitination pathway, leading to increased proliferation of MM cells. We also confirmed the interaction between circRFWD2 and its downstream genes DDB1 and CUL4A, indicating that circRFWD2 could form an E3 ligase complex with other genes to mediate the ubiquitination of p27. Notably, the protein translated by a circular RNA of RFWD2 can also function as an E3 ligase. Our study highlights the potential of circRFWD2 as a biomarker for MM, which may improve the sensitivity and specificity of diagnosis and efficacy analyses.

The Patient-Derived Organoids (PDOs) has demonstrated significant potential in personalized medicine. However, the initial establishment of lung cancer organoids (LCOs), and timely therapeutic recommendations face several challenges. Particularly, the current culture systems have not yet achieved the capability to long-term cultivation of all lung tumor sample sources, including malignant pleural effusion (MPE), which poses significant barriers to the rapid clinical translation of PDOs. Here, we established a LCOs biobank derived from various tumor cell origins and investigated the impact of supplementing culture media with MPE supernatant on organoid formation, culture duration, and drug sensitivity. Our findings indicate that MPE can enhance the successful rate of LCOs by extending the passage number and promoting the initial formation of difficult-to-culture samples, such as those derived from MPE or cell lines that were previously unsuccessful in Airway Organoid (AO) medium. MPE also facilitates the rapid proliferation of LCOs, reducing the culture duration by over 50%. Additionally, LCOs exhibit increased chemoresistance in the presence of MPE, which modifies stem cell distribution and reshapes the internal structure of the organoids. Overall, this study highlights the significance of MPE in facilitating the establishment and maintenance of LCOs, and its potential for translational applications in lung cancer research and personalized.

Despite therapeutic advancements, multiple myeloma (MM) remains incurable. NK cells have emerged as a promising option for the treatment of MM. NK cells are heterogenous and typically classified based on the relative expression of their surface markers (e.g., CD56 and CD16a). These cells elicit an antitumor response in the presence of low mutational burden and without neoantigen presentation via germline-encoded activating and inhibitory receptors that identify the markers of transformation present on the MM cells. Higher NK cell activity is associated with improved survival and prognosis, whereas lower activity is associated with advanced clinical stage and disease progression in MM. Moreover, not all NK cell phenotypes contribute equally toward the anti-MM effect; higher proportions of certain NK cell phenotypes result in better outcomes. In MM, the proportion, phenotype, and function of NK cells are drastically varied between different disease stages; this is further influenced by the bone marrow microenvironment, proportion of activating and inhibitory receptors on NK cells, expression of homing receptors, and bone marrow hypoxia. Antimyeloma therapies, such as autologous stem cell transplant, immunomodulation, proteasome inhibition, and checkpoint inhibition, further modulate the NK cell landscape in the patients. Thus, NK cells can naturally work in tandem with anti-MM therapies and be strategically modulated for improved anti-MM effect. This review article describes immunotypic and phenotypic differences in NK cells along with the functional changes in homeostatic and malignant states and provides expert insights on strategies to harness the potential of NK cells for improving outcomes in MM.

Adoptive T cell therapy is a pivotal strategy in cancer immunotherapy, demonstrating potent clinical efficacy. However, its limited durability often results in primary resistance. High-throughput screening technologies, which include both genetic and non-genetic approaches, facilitate the optimization of adoptive T cell therapies by enabling the selection of biologically significant targets or substances from extensive libraries. In this review, we examine advancements in high-throughput screening technologies and their applications in adoptive T cell therapies. We highlight the use of genetic screening for T cells, tumor cells, and other promising combination strategies, and elucidate the role of non-genetic screening in identifying small molecules and targeted delivery systems relevant to adoptive T cell therapies, providing guidance for future research and clinical applications.

Urothelial carcinoma (UC) of the urinary bladder has significant challenges in treatment due to its diverse genetic landscape and variable response to systemic therapy. In recent years, patient-derived organoids (PDOs) emerged as a novel tool to model primary tumors with higher resemblance than conventional 2D cell culture approaches. However, the potential of organoids to predict therapy response in a clinical setting remains to be evaluated. This study explores the clinical feasibility of PDOs for pharmacotyping in UC. Initially, we subjected tumor tissue specimens from 50 patients undergoing transurethral resection or radical cystectomy to organoid propagation, of whom 19 (38%) yielded PDOs suitable for drug sensitivity assessment. Notably, whole transcriptome-based analysis indicated that PDOs may show phenotypes distinct from their parental tumor tissue. Pharmacotyping within a clinically relevant timeframe [mean of 35.44 and 55 days for non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), respectively] was achieved. Drug sensitivity analyses revealed marked differences between NMIBC and MIBC, with MIBC-derived organoids demonstrating higher chemosensitivity toward clinically relevant drugs. A case study correlating organoid response with patient treatment outcome illustrated the complexity of predicting chemotherapy efficacy, especially considering the rapid acquisition of drug resistance. We propose a workflow of prospective organoid-based pharmacotyping in UC, enabling further translational research and integration of this approach into clinical practice.