Functional effects of neoantigen-producing genes on antitumor immune responses

Abstract

The outgrowth of clones not expressing tumor antigens is a well-known immune evasion mechanism of cancer. Here, we defined constitutive and facultative neoantigens according to the essentiality of the function and expression of their corresponding genes. Constitutive neoantigens are essentially expressed for tumour growth even under immune selection and expected to be derived from genes with high fitness effects as quantified by loss-of-function screening or low degrees of intratumoral heterogeneity as measured by single-cell expression analysis. Multiple cohorts across various cancer types (n=2514) consistently revealed the influence of these gene-level properties on clinical responses to checkpoint blockade. The pretherapy load of and in-therapy reduction in constitutive neoantigens contributed to the clinical benefit. In contrast, poor clinical responses implied immune evasion with an increase in the clonal frequency of facultative neoantigens and a decrease in the expression of dispensable genes. Notably, basal expression levels were irrelevant to the clinical validity of the corresponding neoantigens. These findings were further supported by data from The Cancer Genome Atlas (TCGA) samples (n=2113). Therefore, immune evasion may be minimized by steering antitumor immune responses toward neoantigens from essential genes.