Systematic evaluation of intratumoral and peripheral BCR repertoires in three cancers
Sofia V Krasik,
Ekaterina A Bryushkova,
George V Sharonov,
Daria S Myalik,
Elizaveta V Shurganova,
Dmitry V Komarov,
Irina A Shagina,
Polina S Shpudeiko,
Maria A Turchaninova,
Maria T Vakhitova,
Igor V Samoylenko,
Dimitr T Marinov,
Lev V Demidov,
Vladimir E Zagaynov,
Dmitriy M Chudakov,
Ekaterina O Serebrovskaya
Affiliations
Sofia V Krasik
Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation
Ekaterina A Bryushkova
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation; Department of Molecular Biology, Lomonosov Moscow State University, Moscow, Russian Federation
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation; Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation
Daria S Myalik
Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation; Nizhny Novgorod Regional Clinical Cancer Hospital, Nizhny Novgorod, Russian Federation
Elizaveta V Shurganova
Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation
Dmitry V Komarov
Volga Regional Medical Centre Under Federal Medical and Biological Agency, Nizhny Novgorod, Russian Federation
Irina A Shagina
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
Polina S Shpudeiko
Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russian Federation
Maria A Turchaninova
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
Maria T Vakhitova
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
Igor V Samoylenko
Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of Russian Federation, Moscow, Russian Federation
Dimitr T Marinov
Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of Russian Federation, Moscow, Russian Federation
Lev V Demidov
Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of Russian Federation, Moscow, Russian Federation
Vladimir E Zagaynov
Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation; Nizhny Novgorod Regional Clinical Cancer Hospital, Nizhny Novgorod, Russian Federation
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation; Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russian Federation; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
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.
