The Adaptome as Biomarker for Assessing Cancer Immunity and Immunotherapy

In terms of diagnosing and treating diseases, our adaptive immune system is the "best doctor." It carries out these tasks with unmatched precision, with the help of both T and B cell receptors, our most diverse set of genes, distinguishing one individual from another. It does this by generating autologous extraordinary diversity in the receptors, ranging from 10¹⁵ to 10²⁵ for each chain of the rearranged receptors. By combining multiplex PCR and next-generation sequencing (NGS), we have developed high throughput methods to study adaptive immunity. The adaptome is the sum-total of expressed T and B cell receptor genes in a sample, composed of seven chains, including the alpha/beta and gamma/delta chains for T cells, and heavy/lambda or kappa chains for B cells. Immune repertoire is the sum-total of the individual clonotypes within one chain, including individual complementarity-determining regions (CDR) 3 sequences. In order to reflect the breadth and depth of the true adaptome, the following criteria assessing any method needs to be ascertained: (1) Methods need to be inclusive and quantitative; (2) Analysis should consider what questions need to be addressed and whether bulk or single cell sequencing provide the best tools for assessing the underlying biology and addressing important questions; (3) Measures of clonal diversity are key to understand the underlying structure and providence of the repertoire; and (4) Convergent evolution may allow a surprising degree of homologous or identical CDR3s associated with individual disease entities, creating hope for novel diagnostics and/or disease burden assessments. Integrating studies of the peripheral blood, lymph nodes, and tumor allows dynamic interrogation of the alterations occurring with age, treatment, and response to emergent and established therapies.