识别对免疫检查点阻断有反应的保守性冷肿瘤亚群

The efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. Transforming growth factor-beta (TGF ) is associated with immune-poor, so-called cold tumors whereas loss of its signaling promotes DNA misrepair that could stimulate immune response.

We analyzed transcriptomic data from IMvigor210, The Cancer Genome Atlas, and Tumor Immune Syngeneic MOuse data sets to evaluate the predictive value of high Alt, a score representing low expression of a signature consisting of TGF targets and high expression of genes involved in error-prone DNA repair. The immune context of Alt was assessed by evaluating tumor-educated immune signatures. An ICB-resistant, high Alt preclinical tumor model was treated with a TGF inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control.

We found that a high Alt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high Alt cancers consist of cancer cells in which loss of TGF signaling generates a TGF rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGF inhibition followed by radiotherapy could convert an immune-poor, high Alt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGF inhibition increased activated natural killer (NK) cells, which were required to recruit lymphocytes to respond to ICB in irradiated tumors. NK cell activation signatures were also increased in high Alt, cold mouse and human tumors that responded to ICB.

These studies indicate that loss of TGF signaling competency and gain of error-prone DNA repair identifies a subset of cold tumors that are responsive to ICB. Our mechanistic studies show that inhibiting TGF activity can convert a high Alt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGF , DNA repair, and immune context signatures is a means to prospectively identify patients whose cancers may be converted from cold to hot with appropriate therapy.