Immune response precision customized to tumor adaptive kinetics

Tumor heterogeneity results from the continuous accumulation of mutations in cancer cells. High phenotypic diversity in cancer can reduce the efficacy of precisely targeted adaptive immune responses. To investigate the conditions under which tumor heterogeneity is sufficient for immune evasion, we developed an agent-based model at the level of individual cells. In this model, cancer phenotypes are represented as vectors, with mutation as a random walk on the corresponding phenotypic space. We evaluated various immune activation strategies by modulating the affinity threshold for activation and assessed their impact on tumor clearance rates. First, the model exhibited oscillatory behavior consistent with empirical observation, that we hypothesized was driven by negative frequency dependent selection. Further supporting this mechanism, the variance of cancer phenotypes consistently increases as the cancer population collapses. Finally, we identified conditions favoring either narrow or broad immune activation profiles, in accordance with theoretical predictions. These findings suggest potential strategies for optimizing immunotherapies, such as adoptive cell therapy, by tailoring the antigenic repertoire used to prime immune cells according to the adaptive dynamics of the target tumor population.