A conserved subset of cold tumors responsive to immune checkpoint blockade

We analyzed transcriptomic data from IMvigor210, TCGA and TISMO datasets to evaluate the predictive value of βAlt, a score representing the negative correlation of signatures consisting of transforming growth factor beta (TGFβ) targets and genes involved in error-prone DNA repair. The immune context of βAlt was assessed concomitant evaluation of tumor-educated immune signatures. An ICB-resistant, high βAlt preclinical tumor model was treated with a TGFβ inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control. Results: Here, we show that high βAlt is associated with an immune-poor context yet is predictive of ICB response in both humans and mice. A high βAlt cancer, in which TGFβ signaling is compromised, generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could converted an immune-poor, ICB resistant tumor to an immune-rich, ICB responsive tumor. Mechanistically, TGFβ blockade in irradiated tumors activated natural killer cells that were required to recruit lymphocytes and ICB response. In support of this, natural killer cell activation signatures were also increased in immunepoor mouse and human tumors that responded to ICB