Jiesong Wang

Outcomes in older patients with Hodgkin lymphoma (HL) are compromised by the interplay of patient frailty and disease aggressiveness; however, current stratification tools, including the International Prognostic Score (IPS) and Comprehensive Geriatric Assessment (CGA), lack sufficient prognostic discrimination in the older HL population. We developed and validated a prognostic model integrating metabolic tumor burden and geriatric assessment. In this retrospective study across 14 centers in China between 2006 and 2024, we enrolled 306 patients aged ≥ 60 years with histologically confirmed HL. Patients were randomly partitioned into training ( n = 250) and validation ( n = 56) cohorts. Among the 306 patients, 98 deaths and 130 progression events were recorded during follow‐up. We analyzed 21 candidate variables. The least absolute shrinkage and selection operator (LASSO) analysis and multivariable Cox regression identified five independent predictors for 5‐year overall survival (OS): age > 73 years, baseline 18F‐FDG PET/CT‐derived total lesion glycolysis (TLG) > 200, hemoglobin ≤ 101 g/L, activities of daily living (ADL) dependence, and lymphocyte‐depleted classical Hodgkin lymphoma (LDCHL). A weighted Geriatric Risk Score stratified patients into low‐, intermediate‐, and high‐risk groups. In the validation cohort, the Geriatric Risk Score showed higher discriminatory accuracy than the CGA for both OS (C‐index, 0.770 [95% CI, 0.674–0.867] vs. 0.671 [0.581–0.762]) and PFS (0.761 [0.668–0.853] vs. 0.635 [0.535–0.735]). Among advanced‐stage (Ann Arbor stage III–IV) patients, it also outperformed the IPS‐7 and IPS‐3. By integrating metabolic tumor burden and geriatric assessment, the Geriatric Risk Score improves risk stratification over existing tools in older patients with HL.

Supplementary Figures and Tables

Recurrent abnormalities in immune surveillance–related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain–containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58–CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL.Significance:Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.

Primary large B‐cell lymphoma of immune‐privileged sites (IP‐LBCL), a recently defined entity in WHO‐HAEM5, includes primary diffuse large B‐cell lymphoma (DLBCL) occurring in immune‐privileged areas like the central nervous system (PCNS‐LBCL), vitreoretinal system (PVR‐LBCL), and testis (PT‐LBCL) in immunocompetent patients. This study aimed to identify prognostic factors and create a predictive model for IP‐LBCL. We analyzed 213 newly diagnosed IP‐LBCL patients from April 2006 to April 2023. A nomogram and prognostic index, IPLBCL‐PI, were developed based on elevated LDH, ECOG ≥ 2, and PCNS‐LBCL subtype as independent risk factors for poorer PFS. IPLBCL‐PI categorized patients into four risk groups: low, low‐intermediate, intermediate‐high, and high. The model effectively predicted both PFS and OS in the training cohort and was validated in two external centers. Subgroup analyses showed that IPLBCL‐PI outperformed the Nottingham/Barcelona (NB) and Memorial Sloan Kettering Cancer Center (MSKCC) models in PCNS‐LBCL and was comparable to the International Prognostic Index (IPI) in PT‐LBCL. IPLBCL‐PI is the first prognostic model for IP‐LBCL, offering risk stratification and aiding clinical decision‐making for this rare entity.

Our study aimed to assess the prognostic significance of the interim National Comprehensive Cancer Network International Prognostic Index and PET‐CT‐related parameters for predicting patient outcomes and achieving precise risk stratification for diffuse large B‐cell lymphoma (DLBCL) patients. We retrospectively analyzed the clinicopathological and PET‐CT data of 498 patients diagnosed with DLBCL across three medical centers in China. 418 patients were eligible for subsequent analysis after excluding those with incomplete data and 70% of which were randomly selected as the discovery cohort, whereas the remaining 30% constituted the validation cohort. The impact of candidate factors on survival was assessed via univariate and multivariate Cox proportional hazards models. The area under the curve AUC and C‐index were calculated to assess the predictive performance of models. Univariate and multivariate Cox regression analyses identified changes in total lesion glycolysis (ΔTLG), iNCCN‐IPI, interim abdominal residual disease (iARD) status, and changes in the maximum standardized uptake value (ΔSUVmax) as independent prognostic factors. Leveraging the outcomes of the multivariate analysis, we constructed the iPET‐NCCN‐IPI prognostic model and categorized DLBCL patients into two separate prognostic risk groups based on their computed Risk Scores (RS = 0.90×iNCCN‐IPI + 1.41×ΔTLG + 0.79×ΔSUVmax + 0.83×iARD). The predictive performance of the model was validated by calculating the area under the receiver operating characteristic curve and the C‐index. Notably, compared with other models, the iPET‐NCCN‐IPI demonstrated superior prognostic capability. In conclusion, our study indicates that the iPET‐NCCN‐IPI stratifies DLBCL patients into two distinct prognostic risk groups and surpasses other models in prognostic predictive ability.

Supplementary Figures and Tables

Recurrent abnormalities in immune surveillance–related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain–containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58–CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL.Significance: Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.

Supplementary Figures and Tables

Recurrent abnormalities in immune surveillance–related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain–containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58–CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL. Significance: Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.