Intrinsic RB activation induces tumoral and stromal anti-tumor responses that limit triple-negative breast cancer

The RB tumor suppressor is a key regulator of cell cycle progression that is often inactivated in triple-negative breast cancer (TNBC). Recent studies indicate that drugs activating RB have multiple tumor-suppressing effects on the tumor and the tumor microenvironment (TME). Here, we utilize a constitutively active RB protein incapable of being phosphorylated and inactivated by CDKs (RBΔCDK) to assess the intrinsic sufficiency of RB activation on tumor suppression. Expression of RBΔCDK in TNBC cell lines uniformly inhibited proliferation. Transcriptomic analysis revealed suppression of cell cycle genes and the induction of genes associated with interferon response. Similarly, tumor growth and metastasis were suppressed in RBΔCDK-expressing human xenograft and mouse syngeneic tumor models. RB activation was sufficient to dramatically alter the TME, wherein tumor growth suppression was mediated by CD8⁺ T cells. Together, these data indicate that active RB suppresses TNBC progression in cancer cell-autonomous and non-autonomous mechanisms.