Epidemiological features and prognosis for primary gastrointestinal follicular lymphoma.

Primary gastrointestinal follicular lymphoma (PGI-FL) is a rare extra-nodal lymphoma. Its epidemiology and prognosis remain unclear. We performed a retrospective analysis of eligible patients with 1648 PGI-FL and 34 892 nodal FL (N-FL) in the Surveillance, Epidemiology and End Results (SEER) database. The age-adjusted average annual incidence of PGI-FL was 0.111/100000. The median overall survival (OS) for PGI-FL and N-FL patients was 207 and 165 months respectively. The 5-year diffuse large B-cell lymphoma (DLBCL) transformation rates were 2.1% and 2.6% respectively. Age, sex, grade, Ann Arbor stage, primary site and radiation were independent prognostic factors (p < 0.05). Nomograms were constructed to predict 1-, 5- and 10-year OS and disease-specific survival (DSS). The receiver operating characteristic curves and calibration plots showed the established nomograms had robust and accurate performance. Patients were classified into three risk groups according to nomogram score. In conclusion, the incidence of PGI-FL has increased over the past 40 years, and PGI-FL has a better prognosis and a lower DLBCL transformation rate than N-FL. The nomograms were developed and validated as an individualized tool to predict survival. Patients were divided into three risk groups to assist clinicians in identifying high-risk patients and choosing the optimal individualized treatments.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

Treatment patterns, clinical outcomes and gene mutation characteristics of hepatitis B virus-associated mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an uncommon and incurable B-cell lymphoma subtype that has an aggressive course. Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas, and is characterized by distinct clinical and genetic features. Here, we showed that 9.5% of MCL Chinese patients were hepatitis B surface antigen positive (HBsAg+). Compared to HBsAg-negative (HBsAg-) patients, HBsAg+ MCL patients had a greater incidence of elevated lactate dehydrogenase (LDH), but no difference was observed in the other clinical characteristics, including sex, age, ECOG ps, Ann Arbor stage, MIPI, extranodal involvement and Ki-67. The HD-AraC (high-dose cytarabine) regimen was the main first-line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP-based regimens. Compared with CHOP, the HD-AraC regimen was associated with longer PFS in HBsAg+ patients. Treatment with a Bruton tyrosine kinase inhibitor (BTKi) alone can also cause HBV reactivation. Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg- MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients.

OX40 shapes an inflamed tumor immune microenvironment and predicts response to immunochemotherapy in diffuse large B-cell lymphoma.

OX40 enhances the T-cell activation via costimulatory signaling. However, its molecular characteristics and value in predicting response to immunochemotherapy in DLBCL remain largely unexplored. Here, we performed an integrative analysis of sequencing and multiplex immunofluorescence staining, and discovered abnormally higher expression of OX40 in DLBCL patients. Elevated OX40 could activate T cells leading to a higher immune score for tumor immune microenvironment (TiME). OX40 upregulation simultaneously happened with immune-related genes including PD-1, CTLA4 and TIGIT et,al. Patients with high OX40 expression exhibited a lower Ann Arbor stage and IPI score and more easily achieved a complete response/partial response. The analysis of infiltrated T-cell subset revealed that patients with a greater number of CD4+/OX40+ or CD8+/OX40+ T cells had a longer OS. Our findings indicated that OX40 shapes an inflamed tumor immune microenvironment and predicts response to immunochemotherapy, providing insights for the application of OX40 agonist in DLBCL patients.

Integrative genomic and transcriptomic analysis reveals genetic alterations associated with the early progression of follicular lymphoma.

Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. However, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed. Here, we analysed the clinical-biological features of 415 FL patients to identify variables associated with disease progression within 24 months of first-line therapy (POD24). Patients with B symptoms, elevated lactate dehydrogenase and ß2-microglobulin levels, unfavourable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. HIST1H1D, identified as a driver mutation, was correlated with POD24. Gains of 6p22.2 (HIST1H1D) and 18q21.33 (BCL2) and loss of 1p36.13 (NBPF1) predicted POD24 independent of FLIPI. Gene expression profiling of FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumour necrosis factor), cell cycle regulation (transcription, replication and proliferation) sets and PI3K-AKT-mTOR signalling. This result was further validated with transcriptome-wide information provided by RNA-seq at single-cell resolution. Our study, performed on a large cohort of FL patients, highlights the importance of distinctive genetic alterations and gene expression relevant to disease diagnosis and early progression.

A novel immune-related epigenetic signature based on the transcriptome for predicting the prognosis and therapeutic response of patients with diffuse large B-cell lymphoma.

Epigenetic modifications contribute to lymphomagenesis. Here, we performed an expression clustering analysis and identified two epigenetic-related clusters (EC1 and EC2). EC1 presented abundant TP53, MYD88, HIST1H1D, HIST1H1C, KMT2D and EZH2 mutations and an inferior prognosis. Pathways involved in the regulation of DNA methylation/demethylation, histone methyltransferase activity, and protein methyltransferase activity were significantly enriched in EC1. However, EC2 was frequently accompanied by B2M, CD70 and MEF2B mutations, which presented with enrichments in DNA damage repair, cytokine-mediated and B-cell activated immune signaling, increased levels of CD8+ T-, γδT- and T helper-cells, as well as immune scores and immunogenic cell death (ICD) modulators. According to the prediction, EC1 was more sensitive to vorinostat, serdemetan and navitoclax. However, ruxolitinib, cytarabine and CP466722 were more suitable treatments for EC2. The novel immune-related epigenetic signature exhibits promising clinical predictive value for diffuse large B-cell lymphoma (DLBCL), particularly for guiding epigenetic therapeutic regimens. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) based combination treatment regimens are suggested.

Tracking the evolution of untreated high-intermediate/high-risk diffuse large B-cell lymphoma by circulating tumour DNA.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogenous malignancy, early identification of patients for relapse remains challenging. The potential to non-invasively monitor tumour evolutionary dynamics of DLBCL needs to be further established. In the present study, 17 tumour biopsy and 38 plasma samples from 38 patients with high-intermediate/high-risk DLBCL were evaluated at baseline. Longitudinal blood samples were also collected during therapy. Circulating tumour DNA (ctDNA) was analysed using targeted sequencing based on a gene panel via a recently developed methodology, circulating single-molecule amplification and re-sequencing technology (cSMART). We found that the most frequently mutated genes were tumour protein p53 (TP53; 42·1%), histone-lysine N-methyltransferase 2D (KMT2D; 28·9%), caspase recruitment domain family member 11 (CARD11; 21·1%), cAMP response element-binding protein binding protein (CREBBP; 15·8%), ß2 -microglobulin (B2M; 15·8%), and tumour necrosis factor alpha-induced protein 3 (TNFAIP3; 15·8%). The mutation profiles between ctDNA and matched tumour tissue showed good concordance; however, more mutation sites were detected in ctDNA samples. Either TP53 or B2M mutations before treatment predicted poor prognosis. Analysis of dynamic blood samples confirmed the utility of ctDNA for the real-time assessment of treatment response and revealed that the increases in ctDNA levels and changes in KMT2D mutation status could be useful predictors of disease progression. Our present results suggest that ctDNA is a promising method for the detection of mutation spectrum and serves as a biomarker for disease monitoring and predicting clinical recurrence.

A novel clinical immune-related prognostic model predicts the overall survival of mantle cell lymphoma.

The mantle cell lymphoma (MCL) International Prognostic Index (MIPI) and combined MIPI (MIPI-c) are commonly used for risk classification of MCL patients. However, these indexes lack immune-related parameters. The purpose of this study was to develop a novel prognostic model that integrated clinical and immune parameters. A total of 189 patients with newly diagnosed MCL from January 2010 to June 2020 were enrolled in our study. A nomogram and immune-related prognostic index (IRPI) were established to predict the overall survival (OS) of patients according to univariate and multivariate analyses. Discrimination and calibration were used to compare the prognostic performance of the IRPI, MIPI, and MIPI-c. External validation was performed based on validation dataset (n = 150) from two other centers. The results for the training dataset indicated that B symptoms, platelet count, B2M level, CD4+ T-cell count<26.7% and CD8+ T-cell count>44.2% were predictors for OS. All the prognostic factors were integrated into the nomogram. For the overlap of confidence intervals of each variable, we assigned one point for each factor. The IRPI categorized patients into three risk categories: a score of zero indicated low risk, a score of one or two indicated intermediate risk, and a score of ≥3 indicated high risk. The IRPI showed better discrimination and calibration power than the MIPI and MIPI-c in the training dataset and validation dataset. The novel IRPI is a refined risk stratification index and reflects the strong complementary prognostic effects between clinical and immune parameters in MCL.

Risk factors for POD24 in patients with previously untreated follicular lymphoma: a systematic review and meta-analysis.

Progression of disease within 24 months (POD24) is strongly associated with a poor outcome in patients with follicular lymphoma (FL). Our study aimed to identify the potential risk factors for POD24 in patients with FL. Medline, EMBASE and the Cochrane Library were systematically searched from the earliest record to September 2020. Studies investigating the prognostic factors for POD24 in patients with newly diagnosed grade 1-3a FL were included. Among 10,014 pieces of literature, a total of 90 studies investigating 82 risk factors were included for qualitative analysis. Meta-analyses were performed in 31 studies with 11 factors. Results showed that elevated sIL-2R, ß2m and LDH, total metabolic tumour volume > 510 cm3, vitamin D < 20 ng/mL, grade 3a and lymphoma-associated macrophages/high-power field ≥ 15 were significantly associated with an increased risk of POD24. No significant association was found between POD24 and the ALC/AMC ratio, sex, T effector signature or EZH2 genetic alteration. Additionally, minimal residual disease, Ki-67, PD-1 and TP53 were analysed narratively. Overall, this is the first study that comprehensively analysed the prognostic factors associated with POD24 in FL patients. We have confirmed the significance value of several common prognostic factors as well as others not commonly included in clinical study, helping to construct an integrated and more efficient model.

Reduced radiotherapy clinical benefit for primary Waldeyer's ring diffuse large B-cell lymphoma in the rituximab era.

This study aimed to identify the prognostic factors in patients with Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL), comparing the efficacy of radiotherapy (RT) for the WR-DLBCL patients in the pre-rituximab and rituximab eras. We conducted a retrospective analysis of 134 patients diagnosed with WR-DLBCL. Univariate and multivariate analyses were performed to identify the prognostic factors for WR-DLBCL. Then, we divided these patients into the rituximab plus chemotherapy group (R-chemotherapy) (n = 88) and chemotherapy group (n = 46), and the Kaplan-Meier and Cox regression model analyses were applied to investigate the treatment value of RT in both the groups. Multivariate analysis revealed international prognostic index (IPI) ≥ 3 and chemotherapy without rituximab as significant risk factors for the progression-free survival (PFS, IPI ≥ 3: p = 0.001; chemotherapy without rituximab: p = 0.002) and overall survival (OS, IPI ≥ 3, p < 0.001; chemotherapy without rituximab, p = 0.024). Rituximab combined with chemotherapy significantly improved PFS (p = 0.002) and OS (p = 0.006) in these patients. RT did not significantly contribute to the survival in the overall cohort analysis, whereas in the subgroup analysis, RT significantly improved the PFS (p = 0.025) and OS (p = 0.029) for the patients in the chemotherapy group, but not in the R-chemotherapy group. In conclusion, the WR-DLBCL patients could benefit from RT in the pre-rituximab era, whereas the addition of rituximab to chemotherapy significantly improved the survival of WR-DLBCL patients, and the clinical benefit of RT was reduced.

Biomimetic black phosphorus quantum dots-based photothermal therapy combined with anti-PD-L1 treatment inhibits recurrence and metastasis in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive malignant disease with a high rate of recurrence and metastasis, few effective treatment options and poor prognosis. Here, we designed and constructed a combined photothermal immunotherapy strategy based on cancer cell membrane-coated biomimetic black phosphorus quantum dots (BBPQDs) for tumor-targeted photothermal therapy and anti-PD-L1 mediated immunotherapy. RESULTS: BBPQDs have good photothermal conversion efficiency and can efficiently target tumor cells through homologous targeting and tumor homing. Under near infrared irradiation, we found that BBPQDs kill tumors directly through photothermal effects and induce dendritic cells maturation. In vivo studies have confirmed that the combined photothermal immunotherapy strategy displays a stronger antitumor activity than anti-PD-L1 monotherapy. In addition, BBPQDs-mediated photothermal therapy in combination with anti-PD-L1 treatment inhibit tumor recurrence and metastasis by reprograming the immunosuppressive tumor microenvironment into an immune-active microenvironment, and promoting the local and systemic antitumor immune response. We further found that the combined photothermal immunotherapy strategy can produce an immune memory effect against tumor rechallenge. CONCLUSIONS: This study provides a novel therapeutic strategy for inhibiting the recurrence and metastasis of TNBC, with broad application prospects.

Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma.

Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.

Combination of baseline total metabolic tumor volume measured on FDG-PET/CT and ß2-microglobulin have a robust predictive value in patients with primary breast lymphoma.

The aim was to build a prognostic model to stratify patients at diagnosis into different risk categories. We investigated the prognostic value of functional PET parameters and clinical features in 64 primary breast lymphoma (PBL) patients. With a median follow-up of 60 months, 5-year progression-free survival (PFS) and overall survival (OS) was 62.5% and 73.4%. In multivariate analysis, baseline total metabolic tumor volume (TMTV0) and ß2-microglobulin remained more reliable predictors of survival than other prognostic factors. The optimal TMTV0 cut-off value was 90 cm3 . Among 29 patients with high TMTV0, 5-year PFS and OS were 44.8% and 62.1%, respectively, while 5-year PFS and OS of 35 patients with low TMTV0 were 74.3% and 85.7%, respectively. TMTV0 combined with ß2-microglobulin identified three groups with very different prognosis, including low-risk group with low TMTV0 and ß2-microglobulin≤normal (n = 30), intermediate-risk group with high TMTV0 or ß2-microglobulin>normal (n = 20), and high-risk group with high TMTV0 and ß2-microglobulin>normal (n = 14). In the three groups, 5-year PFS rates were 80%, 55% and 28.6% (P = .003), and 5-year OS rates were 90%, 65%, and 50% (P = .023) respectively. We established a new prognostic model through TMTV0 and ß2-microglobulin, and can divide PBL at diagnosis into different risk categories.

Tumor CD73/A2aR adenosine immunosuppressive axis and tumor-infiltrating lymphocytes in diffuse large B-cell lymphoma: correlations with clinicopathological characteristics and clinical outcome.

Novel immune checkpoint blockades, including those targeting CD73 and A2aR, are being evaluated in malignancies in clinical trials. Here, we investigated the expression of CD73 and A2aR as well as tumor-infiltrating lymphocytes (TILs), and analyzed their correlations with clinicopathological characteristics and survival in diffuse large B-cell lymphoma (DLBCL). We found that CD73 expression on tumor cells, rather than the total protein and gene levels of CD73, was associated with survival. Patients with CD73+ /Pax-5+ (median survival, 57.8 months; 95% CI, 46.4-69.3) experienced significantly poorer outcomes than those with CD73- /Pax-5+ (median survival, 73.5 months; 95% CI, 65.9-81.2). Additionally, A2aR expression on both total TILs and CD8+ TILs was correlated with survival. Patients with A2aR+ TILs (median survival, 53.3 months; 95% CI, 40.6-66.0) had a significantly shorter survival time than patients with A2aR- TILs (median survival, 74.5 months; 95% CI, 67.5-81.5). Spearman's rank test showed that CD73 expression on tumor cells was positively correlated with A2aR expression on TILs (R = 0.395, p = 0.001). We further found that patients could be more precisely stratified through the combination of CD73 tumor cell expression and A2aR TILs expression, and patients with CD73+ /Pax-5+ and A2aR+ TILs experienced the worst outcome. We also revealed that patients with CD73+ /Pax-5+ and low CD8+ TILs or low absolute lymphocyte counts had unfavorable outcomes. Overall, our findings uncovered that patients with CD73+ on tumor cells as well as A2aR+ on TILs or low CD8+ TILs exhibited inferior survival, supporting potential combination strategies using CD73/A2aR immunosuppressive blockades as treatment options for DLBCL patients.

Plasma soluble programmed death ligand 1 levels predict clinical response in peripheral T-cell lymphomas.

Immune checkpoints, including PD-1/PD-L1, play an important role in immunosuppression in various malignancies. Elevated levels of soluble programmed death ligand 1 (sPD-L1) are associated with worse prognosis in multiple myeloma and diffuse large B cell lymphoma. Herein, the purpose of this study is to investigate the relationships between plasma sPD-L1 levels and clinical response in peripheral T-cell lymphoma (PTCL) patients. A total of 37 PTCL patients and 20 healthy volunteers were enrolled. Peripheral blood from patients was collected prior to systemic therapy. Plasma levels of sPD-L1 and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in tissues was detected by immunohistochemistry (IHC). Clinical response for patients was evaluated. ONCOMINE database analyses showed that PD-L1 mRNA expression was significantly upregulated in PTCLs. The median sPD-L1 level was 0.729 ng/mL for 20 healthy volunteers and 1.696 ng/mL for 37 PTCL patients which was significantly higher than that in healthy volunteers (0.000). The sPD-L1 level was positively correlated with IFN-γ level (0.000, r = 0.849) and was also positively associated with clinical staging (0.045), LDH level (0.003), and ß2-MG level (0.045). Patients with high sPD-L1 level had lower overall response rate than those with low sPD-L1 level (88.9% vs 50.0%, 0.022) and tended to have poorer PFS and OS. PD-L1 expression in tissues matched very well with the sPD-L1 level in PTCL patients. In conclusion, PTCL patients had higher sPD-L1 level compared with healthy volunteers. High sPD-L1 level was correlated with worse clinical response, suggesting that sPD-L1 level was an underlying plasma biomarker to predict the prognosis for PTCL patients.

Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2 Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2 Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype.

Immunochemotherapeutic increase of peripheral absolute monocyte count predicts interstitial pneumonia in lymphoma patients.

Interstitial pneumonia (IP) is one of the potentially fatal adverse events for lymphoma patients undergoing immunochemotherapy. However, the risk factors and predictive markers remain unclear for this complication. This retrospective study aims to explore whether the change of absolute monocyte count (AMC) during immunochemotherapy is correlated with IP occurrence and progression. A total of 500 lymphoma patients receiving immunochemotherapy from 2014 to 2016 were enrolled in this investigation. Interstitial pneumonia was generally diagnosed as diffused pulmonary interstitial infiltrates on computed tomography images in conjunction with respiratory symptoms or pulmonary function test, which is also adopted as a diagnosing tool of IP in this study. Among the total 500 participating patients, 40 patients were diagnosed as IP, which account for 8% of the total subjects. The median number of chemotherapy cycles for those patients prior to IP occurrence is 4. This research suggests that the increase of peripheral AMC over 0.565 × 109 /L after 2 cycles of immunochemotherapy is a great potential to develop IP. Using the method of multivariate analysis, lymphoma lung involvement and high AMC after 2 cycles of immunochemotherapy were identified as independent risk factors for IP. Most IP patients with sustained AMC elevation (>0.575 × 109 /L at IP onset) accompanied severe pulmonary symptoms, while those with AMC fall-back might tolerate subsequent immunochemotherapy. Thus, this study concludes that early increase of AMC during immunochemotherapy in lymphoma patients with lung involvement suggested a great potential to develop IP. Dynamic changes in AMC may serve as a predictive marker for IP severity and a guide for treatment adjustment for both tumor and pulmonary injuries.

Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mechanistic target of rapamycin kinase inhibitors in aggressive B-cell lymphomas.

Mechanistic target of rapamycin (mTOR) complex 1 is a central integrator of nutrient and growth factor inputs that controls cell growth in eukaryotes. The second generation of mTOR kinase inhibitors (TORKi), directly targeting the mTOR catalytic site, are more effective than rapamycin and its analogs in cancer treatment, particularly in inducing apoptosis. However, the mechanism underlying the cytotoxic effect of TORKi remains elusive. Herein, we demonstrate that TORKi-induced apoptosis is predominantly dependent on the loss of mTOR complex 1-mediated 4EBP activation. Knocking out RICTOR, a key component of mTOR complex 2, or inhibiting p70S6K has little effect on TORKi-induced apoptosis. Conversely, increasing the eIF4E:4EBP ratio by either overexpressing eIF4E or knocking out 4EBP1/2 protects lymphoma cells from TORKi-induced cytotoxicity. Furthermore, downregulation of MCL1 expression plays an important role in TORKi-induced apoptosis, whereas BCL-2 overexpression confers resistance to TORKi treatment. We further show that the therapeutic effect of TORKi in aggressive B-cell lymphomas can be predicted by BH3 profiling, and improved by combining it with pro-apoptotic drugs, especially BCL-2 inhibitors, both in vitro and in vivo Taken together, the study herein provides mechanistic insight into TORKi cytotoxicity and identified a potential way to optimize its efficacy in the clinical treatment of aggressive B-cell lymphoma.