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 ßAlt, a score representing the negative correlation of signatures consisting of transforming growth factor beta (TGFß) targets and genes involved in error-prone DNA repair. The immune context of ßAlt was assessed concomitant evaluation of tumor-educated immune signatures. An ICB-resistant, high ßAlt preclinical tumor model was treated with a TGFß inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control. Results: Here, we show that high ßAlt is associated with an immune-poor context yet is predictive of ICB response in both humans and mice. A high ßAlt cancer, in which TGFß signaling is compromised, generates a TGFß rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFß inhibition followed by radiotherapy could converted an immune-poor, ICB resistant tumor to an immune-rich, ICB responsive tumor. Mechanistically, TGFß 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 Overall design: RNASeq profiling of 15 F2 mTDT from family F mouse mammary tumors in the BALB/cJ strain. The animals were treated with  TGFß inhibitor, radiation, and/or immune checkpoint blockage (ICB) inhibitor. Tumors were collected 7 days following treatment for RNA profiling.