The Effects of Clonal Heterogeneity on Cancer Immunosurveillance

Intratumor heterogeneity (ITH) is associated with tumor progression in several clinical and experimental settings and contributes to therapeutic resistance. Its relation to cancer immunosurveillance is complex. Clonally heterogeneous tumors are associated with decreased immunosurveillance and are less responsive to immune checkpoint inhibition, but the mechanistic basis underlying these observations remains unclear. One possibility is that tumors that are under active immunosurveillance are relatively homogeneous because immunosurveillance prevents the outgrowth of immunogenic subclones. Alternatively, high ITH might directly impair immunosurveillance due to lower dosages of subclonal antigens, competition between antigens and immunodominance, the induction of detrimental T cell differentiation programs, or negative feedback loops. Here we review the evidence for these scenarios and outline hypotheses that could underlie the negative association between clonal heterogeneity and cancer immunosurveillance.