The 29th European Hematology Association (EHA) Annual Meeting took place from June 13-16, 2024, in Madrid, Spain. At this prestigious event, Professor Huilai Zhang's team from Tianjin Medical University Cancer Institute and Hospital presented several research studies in poster sessions, highlighting the clinical features, genetic variations, and histological grading of follicular lymphoma. Their work offers a deeper understanding of the disease. Additionally, Professor Zhang's team delved into the epidemiological characteristics and prognosis of primary gastrointestinal follicular lymphoma, providing new insights for diagnosing and treating this rare disease. In the field of mantle cell lymphoma (MCL) treatment, their study on the Orelabrutinib-Lenalidomide-Rituximab regimen brings new hope to patients. Of particular note is their research on the impact of CD58 genetic alterations in diffuse large B-cell lymphoma (DLBCL), which enhances our understanding of the tumor immune microenvironment and suggests new approaches for personalized treatment. To provide a comprehensive overview of these research findings,Oncology Frontier - Hematology Frontier invited Professor Huilai Zhang to share the details.1. CD58 Genetic Alterations Govern Antitumor Immune Responses by Regulating PD-L1 and IDO via the LYN/CD22/SHP1 Axis in DLBCL (Abstract No. P1226)
Background
In the development of diffuse large B-cell lymphoma (DLBCL), recurrent abnormalities in genes related to immune surveillance play a crucial role. Previous studies have shown that CD58, a key adhesion molecule and ligand for the T-cell co-stimulatory molecule CD2, frequently mutates or is deleted in certain hematologic malignancies. Aberrant expression of CD58 may lead to tumor cells evading T/NK cell-mediated immune surveillance. CD58 downregulation or loss is associated with resistance to immune checkpoint blockade (ICB) therapy in melanoma and CAR-T therapy in B-cell malignancies. However, the role of CD58 in cancer is not fully understood.
Objective
This study aims to comprehensively characterize CD58 genetic alterations in DLBCL, uncover the multiple roles of CD58 in antitumor immunity, and provide insights into potential therapeutic strategies.
Methods
Comprehensive analysis of CD58 genetic characteristics was performed through targeted deep sequencing (n=176), whole-exome sequencing (n=38), and RNA sequencing (n=162) in newly diagnosed DLBCL patients. To investigate the mechanistic impact of CD58 alterations on co-inhibitory molecule expression and immune cell functions, bulk and single-cell RNA sequencing analyses were conducted, along with in vitro and in vivo experiments.
Results
CD58 mutation rate was found to be 9.1%, with 61.1% of mutations occurring in exon 2, potentially disrupting CD58-CD2 binding. Co-mutation analysis showed higher frequencies of KMT2D, CD79B, and MYD88 mutations in CD58-mutant patients (P<0.05). CD58 copy number loss rate was 44.7%, and both mutations and copy number losses tended to reduce CD58 mRNA expression. Patients with CD58 mutations, copy number losses, or low expression had lower complete response rates to R-CHOP treatment and significantly poorer PFS and OS.
To explore the impact of CD58 on the DLBCL microenvironment, bulk and single-cell RNA-seq revealed increased NK cells, activated CD4+/CD8+ T cells, and decreased exhausted CD8+ T cells in CD58-high expressing samples. In vitro co-culture and in vivo xenograft models showed that CD58 downregulation or mutation in DLBCL cells inhibited T-cell proliferation and impaired CAR-T-mediated killing. Interestingly, CD58 downregulation or mutation in DLBCL cells led to upregulation of PD-L1 and IDO, indicating dual effects on T cells, including loss of CD2 co-stimulatory signals and increased inhibitory signals via PD-L1 and IDO.
Further investigation revealed that CD58 downregulation or mutation promoted JAK2/STAT1 phosphorylation, enhancing PD-L1 and IDO expression. Co-immunoprecipitation (Co-IP) identified CD58 interaction with LYN, which phosphorylates the inhibitory receptor CD22’s ITIM, recruiting and activating SHP1. CD58 downregulation or mutation inhibited the LYN/CD22/SHP1 axis, promoting JAK2/STAT1 activation and upregulation of PD-L1 and IDO.
To overcome the dual effects of CD58 alterations, anti-PD-L1 antibody or IDO inhibitor combined with recombinant CD58-Fc fusion protein was added to co-cultured cells. The combined approach reversed the inhibitory effects of CD58 downregulation or mutation on T-cell proliferation and restored sensitivity to CAR-T-mediated killing.
Conclusion
Our study comprehensively characterizes CD58 genetic alterations in DLBCL and demonstrates that CD58 downregulation or mutation primarily regulates PD-L1 and IDO via the LYN/CD22/SHP1 axis. Additionally, we explore strategies to counteract the multifaceted effects of CD58 alterations, providing new insights for personalized treatment in DLBCL patients with CD58 mutations or deletions.
2. The Safety and Efficacy of Obinutuzumab Plus Chemotherapy Therapy for Untreated Follicular Lymphoma: A Chinese Retrospective Analysis (Abstract No. P2069)
Background
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (iNHL). The GALLIUM study showed that obinutuzumab (G)-based chemotherapy (G-chemo) significantly improved survival benefits compared to rituximab (R)-based chemotherapy (R-chemo) in untreated FL patients. However, the study did not include Chinese patients treated with the G-chemo regimen.
Objective
This multicenter retrospective comparative study aims to analyze the efficacy and safety of the GB (obinutuzumab plus bendamustine) regimen and G-CHOP (obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, prednisone) regimen in Chinese patients.
Methods
From 2020 to 2023, 301 newly diagnosed FL patients were retrospectively collected. The normality of continuous variables was tested using the Shapiro-Wilk test. Differences in baseline characteristics between GB and G-CHOP patients were tested using t-tests and Kruskal-Wallis rank-sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical variables.
Results
A total of 153 FL patients received the GB regimen, and 148 received G-CHOP as first-line treatment. Except for grading (P<0.001), baseline characteristics showed no other statistical differences between the groups. Among the 211 patients who completed induction therapy and were evaluable for response, 203 achieved a response (overall response rate, ORR, 96.21%), and 160 achieved a complete response (complete response rate, CRR, 75.83%). No differences in efficacy were observed between the treatment regimens.
Multivariate analysis showed that treatment regimen, sex, age, KI67 ratio, grade, stage, ECOG PS score, B symptoms, bulky disease, FLIPI 1, and FLIPI 2 were not associated with CR or ORR.
Safety data were collected from 230 patients, showing no new safety signals compared to the GALLIUM study data.
Conclusion
This is the largest analysis of the GB regimen versus G-CHOP regimen for FL in China to date. Overall, the G-based regimens demonstrated excellent therapeutic efficacy and manageable safety, with consistent results for GB and G-CHOP.
