Circulating B-Cell Receptor (BCR) Repertoire Diversity as a Biomarker of Immunotherapy Response

The immunotherapy of cancer has revolutionized the treatment of oncologic cancer, but the patient response has been very heterogeneous and this has greatly raised the need to develop strong, minimally invasive, biomarkers that predict and monitor the reaction to the treatment. Although T-cell receptor (TCR) repertoire profiling has enjoyed much focus, recent studies have demonstrated that the variety of circulating B-cell receptor (BCR) repertoire is critical and understudied in determining antitumor immunity and immunotherapy response. With the current development of high-throughput immune repertoire sequencing, BCR diversity, clonality, somatic hypermutation, and lineage evolution can now be comprehensively characterized using a peripheral blood sample. The current article assesses the circulating BCR repertoire diversity as an immunotherapy responsiveness biomarker by synthesising the recent findings of immune checkpoint blockade, cancer vaccines, and combination immunotherapies biomarkers. We discuss methodological platforms of BCR sequencing, analytical diversity measures and computing methods of repertoire architecture. The existing data shows that the responders to immunotherapy tend to be characterized by either dynamic BCR repertoire remodelling, clonal amplification of tumour-surveillance B cells, and changes in indices of diversity throughout therapy. Moreover, peripheral BCR signatures have been linked to the treatment efficacy, immune-related adverse events, as well as long-term immune memory formation. We also comment on technical and biological confounders, which are sequencing depth, sampling time, tumor heterogeneity and immune compartmentalization. The problems of standardization and reproducibility are mitigated, and the novel methods of single-cell and multi-omics that increase interpretability are described. Lastly, we suggest a translational system of applying circulating BCR repertoire measures to foresee biomarker and clinical trial layout.