Krasik Sofia V, Bryushkova Ekaterina A, Sharonov George V, Myalik Daria S, Shurganova Elizaveta V, Komarov Dmitry V, Shagina Irina A, Shpudeiko Polina S, Turchaninova Maria A, Vakhitova Maria T, Samoylenko Igor V, Marinov Dimitr T, Demidov Lev V, Zagaynov Vladimir E, Chudakov Dmitriy M, Serebrovskaya Ekaterina O
Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation.
Elife. 2025 Jan 20;13:RP89506. doi: 10.7554/eLife.89506.
The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.
目前对癌症患者体液免疫反应的理解表明，肿瘤可能被肿瘤外源性的弥漫性B细胞浸润，或者可能形成有组织的淋巴结构，在这些结构中，体细胞超突变和抗原驱动的选择在局部发生。这些过程被认为受到肿瘤微环境通过分泌因子和偏向性细胞间相互作用的显著影响。为了探索这种影响的表现，我们使用深度无偏免疫球蛋白谱分析，并系统地描述了14例患有三种人类癌症的患者循环中的B细胞、引流淋巴结（引流LN）和肿瘤之间的关系。我们证明引流LN以不同方式参与与肿瘤部位的相互作用，并且即使在单个淋巴结（LN）的不同部分之间也存在显著的异质性。接下来，我们证实并详细阐述了先前关于肿瘤内免疫球蛋白异质性的观察结果。我们鉴定出相对于引流LN和血液在肿瘤中扩增的B细胞受体（BCR）克隆型，并观察到这些肿瘤扩增的克隆型比未扩增的（普遍存在的）克隆型超突变程度更低。此外，我们观察到与循环B细胞相比，肿瘤浸润B细胞中BCR重链互补决定区3（CDR-H3）的特性向不太成熟和不太特异的BCR库转变，这可能表明肿瘤微环境（TME）中对产生抗体的B细胞发育的控制不太严格。此外，我们发现库水平的证据表明B细胞在激活体细胞超突变（SHM）之前可能根据其CDR-H3理化性质被选择。总之，我们的工作勾勒出肿瘤BCR库相对于非肿瘤组织差异的大致情况，并指出了SHM过程的意外特征。
