Tumour neoantigen heterogeneity thresholds provide a time window for combination immunotherapy
Guim Aguadé‐Gorgorió, Ricard V. Solé
Abstract
Following the advent of cancer immunotherapy, increasing insight has been gained on the role of mutational load and neoantigens as key ingredients in T cell recognition of malignancies. However, not all highly mutational tumours react to immune therapies, and initial success is often followed by eventual relapse. Heterogeneity in the neoantigen landscape of a tumour might be key in the failure of immune surveillance. In this work, we present a mathematical framework to describe how neoantigen distributions shape the immune response. The model predicts the existence of an antigen diversity threshold level beyond which T cells fail at controlling heterogeneous tumours. Incorporating this diversity marker adds predictive value to antigen load for two cohorts of anti-CTLA-4 treated melanoma patients. Furthermore, our analytical approach indicates rapid increases in epitope heterogeneity in early malignancy growth following immune escape. We propose a combination therapy scheme that takes advantage of preexisting resistance to a targeted agent. The model indicates that the selective sweep for a resistant subclone reduces neoantigen heterogeneity, and we postulate the existence of a time window before tumour relapse where checkpoint blockade immunotherapy can become more effective.