A conserved subset of cold tumors responsive to immune checkpoint blockade
Authors: Moore Jade , Gkantalis Jim , Guix Ines , Chou William , Yuen Kobe , Lazar Ann A. , Spitzer Mathew , Combes Alexis J. , Barcellos-Hoff Mary Helen 
Published: March 2024

AbstractBackgroundThe efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. At the time of diagnosis, patients with lymphocyte-infiltrated cancers are the most responsive to ICB, yet a considerable fraction of patients have immune-poor tumors.MethodsWe 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 by evaluating 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.ResultsHere, 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 convert 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 to respond to ICB. In support of this, natural killer cell activation signatures were also increased in immune-poor mouse and human tumors that responded to ICB.ConclusionsThese studies suggest that loss of TGFβ competency identifies a subset of cold tumors that are candidates for ICB. Our mechanistic studies show that inhibiting TGFβ activity converts high βAlt, cold tumors into ICB-responsive tumors via NK cells. Thus, a biomarker consisting of combined TGFβ, DNA repair, and immune context signatures provides a means to prospectively identify patients whose cancers may be converted from ‘cold’ to ‘hot,’ which could be exploited for therapeutic treatment.What is already known on this topic–For some cancer patients, response to ICB provides durable tumor control. Current biomarkers are insufficient to reliably predict the immunotherapy response for most patients, particularly those whose tumors lack lymphocytic infiltration.What this study adds–The βAlt score, which reports a DNA damage deficiency caused by lack of TGFβ signaling, predicts response to ICB in clinical trial data from IMvigor210 metastatic bladder cancer patients and for melanoma patients. Notably, transcriptomic assessment of the immune context shows that these are immune-poor, so-called “cold” tumors. Preclinical modeling indicates that alleviating TGFβ inhibition of NK cells is critical to relieving immunosuppression.How this study might affect research, practice or policy–Our work identifies a novel tumor phenotype consisting of cancer cells that have lost TGFβ signaling and gained error-prone DNA repair embedded in a TGFβ rich, immune-poor microenvironment, which is conserved across cancer types in humans and among preclinical tumor models. Patients whose immune-poor tumors have high βAlt scores are strong candidates for ICB and radiotherapy combinations that may be further augmented by TGFβ inhibition. Hence, the βAlt score can be used to stratify immune-poor cancer patients for optimal therapeutic strategies.