ArticlebioRxiv : the preprint server for biology2025
A conserved subset of cold tumors responsive to immune checkpoint blockade.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: The 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. Methods: 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 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. 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 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. Conclusions: These 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.
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