Tumuluru Sravya, Godfrey James K, Cooper Alan, Yu Jovian, Chen Xiufen, MacNabb Brendan W, Venkataraman Girish, Zha Yuanyuan, Pelzer Benedikt, Song Joo, Duns Gerben, Sworder Brian J, Raj Sandeep, Bolen Christopher, Penuel Elicia, Postovalova Ekaterina, Kotlov Nikita, Bagaev Aleksander, Fowler Nathan, Shouval Roni, Smith Sonali M, Alizadeh Ash A, Steidl Christian, Kline Justin
Biological Sciences Division, Committee on Cancer Biology, The University of Chicago, Chicago, IL.
Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA.
Blood. 2025 May 22;145(21):2460-2472. doi: 10.1182/blood.2024025355.
Most patients with diffuse large B-cell lymphoma (DLBCL) treated with immunotherapies such as bispecific antibodies (BsAbs) 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 multiomics approach was applied to multiple large independent data sets to characterize DLBCL immune environments and to define their association with tumor cell-intrinsic genomic alterations and outcomes to CD19-directed CAR T-cell and CD20 × CD3 BsAb therapies. This approach effectively segregated DLBCLs into 4 immune quadrants (IQs) defined by cell-of-origin and immune-related gene set expression scores. These quadrants consisted of activated B cell-like (ABC) hot, ABC cold, germinal center B cell-like (GCB) hot, and GCB cold DLBCLs. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute significantly to orchestrating unique DLBCL immune environments. For instance, SOCS1 loss-of-function mutations were significantly enriched among GCB hot DLBCLs, identifying a putative subset of inflamed DLBCLs that may be inherently susceptible to immunotherapy. In patients with relapsed/refractory DLBCL, DLBCL-IQ assignment correlated significantly with clinical benefit with a CD20 × CD3 BsAb (N = 74), but not with CD19-directed CAR T cells (Stanford, N = 51; Memorial Sloan Kettering Cancer Center, N = 69). Thus, DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and suggests the endogenous immune environment has a more significant impact on outcomes to BsAb than CAR T-cell treatment.
大多数接受双特异性抗体（BsAbs）或嵌合抗原受体（CAR）T细胞等免疫疗法治疗的弥漫性大B细胞淋巴瘤（DLBCL）患者未能实现持久的治疗反应，这凸显了深入了解调节免疫环境和治疗反应机制的必要性。在此，采用综合多组学方法对多个大型独立数据集进行分析，以表征DLBCL免疫环境，并确定其与肿瘤细胞内在基因组改变以及针对CD19的CAR T细胞和CD20×CD3 BsAb疗法疗效之间的关联。这种方法有效地将DLBCL分为4个免疫象限（IQs），由起源细胞和免疫相关基因集表达分数定义。这些象限包括活化B细胞样（ABC）热型、ABC冷型、生发中心B细胞样（GCB）热型和GCB冷型DLBCL。每个IQ中均富集了复发性基因组改变，表明淋巴瘤细胞内在改变对构建独特的DLBCL免疫环境有显著贡献。例如，功能丧失的SOCS1突变在GCB热型DLBCL中显著富集，确定了一组可能对免疫疗法固有敏感的炎症性DLBCL。在复发/难治性DLBCL患者中，DLBCL-IQ分类与使用CD20×CD3 BsAb（N = 74）的临床获益显著相关，但与针对CD19的CAR T细胞（斯坦福大学，N = 51；纪念斯隆凯特琳癌症中心，N = 69）无关。因此，DLBCL-IQ为概念化DLBCL免疫格局提供了一个新框架，并表明内源性免疫环境对BsAb疗效的影响比对CAR T细胞治疗的影响更大。
