To study the role of tumor-infiltrating B cells, Hu and Zhang et al. modified the TRUST algorithm to assemble over 30 million CDR3 sequences of the B cell receptor immunoglobulin heavy chain using bulk tumor RNAseq data from TCGA, spanning 32 cancer types. The researchers observed widespread B cell clonal expansion within tumors and identified a relationship between the clonal expansion of B cells with IgG3-1 class switches and survival in patients with high somatic hypermutation rates. They also identified possible evidence of elevated ADCC and activation of tumor escape mechanisms coinciding with B cell response.
Tumor-infiltrating B cells are an important component in the microenvironment but have unclear anti-tumor effects. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin hypervariable regions from bulk tumor RNA-sequencing data. TRUST assembled more than 30 million complementarity-determining region 3 sequences of the B cell heavy chain (IgH) from The Cancer Genome Atlas. Widespread B cell clonal expansions and immunoglobulin subclass switch events were observed in diverse human cancers. Prevalent somatic copy number alterations in the MICA and MICB genes related to antibody-dependent cell-mediated cytotoxicity were identified in tumors with elevated B cell activity. The IgG3-1 subclass switch interacts with B cell-receptor affinity maturation and defects in the antibody-dependent cell-mediated cytotoxicity pathway. Comprehensive pancancer analyses of tumor-infiltrating B cell-receptor repertoires identified novel tumor immune evasion mechanisms through genetic alterations. The IgH sequences identified here are potentially useful resources for future development of immunotherapies.