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Updated: May 24, 2025
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Published on: June 12, 2021
Identification of a conserved subset of cold tumors responsive to immune checkpoint blockade
Jade Moore1, Jim Gkantalis1, Ines Guix1
1Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
Background:
The efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. Transforming growth factor-beta (TGFβ) is associated with immune-poor, so-called cold tumors whereas loss of its signaling promotes DNA misrepair that could stimulate immune response.
Methods:
We analyzed transcriptomic data from IMvigor210, The Cancer Genome Atlas, and Tumor Immune Syngeneic MOuse data sets to evaluate the predictive value of high βAlt, a score representing low expression of a signature consisting of TGFβ targets and high expression of 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:
We found that a high βAlt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high βAlt cancers consist of cancer cells in which loss of TGFβ signaling generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, high βAlt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ 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 βAlt, cold mouse and human tumors that responded to ICB.
Conclusions:
These studies indicate that loss of TGFβ 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 TGFβ activity can convert a high βAlt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGFβ, 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.
Insights
High TGFβ signaling loss and DNA repair alterations identify cold tumors responsive to immune checkpoint blockade (ICB). Inhibiting TGFβ converts cold tumors to ICB-responsive ones by activating natural killer (NK) cells.
Area of Science:
- Oncology
- Immunology
- Cancer Genomics
Background:
- Immune checkpoint blockade (ICB) efficacy relies on restoring anti-cancer immune responses.
- Transforming growth factor-beta (TGFβ) signaling is linked to immune-poor ('cold') tumors.
- Loss of TGFβ signaling may promote DNA misrepair, potentially stimulating anti-tumor immunity.
Purpose of the Study:
- To evaluate the predictive value of a high βAlt score (low TGFβ target gene expression, high DNA repair gene expression) for ICB response.
- To investigate the immune context associated with the βAlt score.
- To assess the efficacy of TGFβ inhibition, radiation, and ICB in an ICB-resistant preclinical model.
Main Methods:
- Analysis of transcriptomic data from human and mouse tumor datasets (IMvigor210, TCGA, TIM).
- Assessment of immune signatures in relation to the βAlt score.
- Preclinical treatment of a high βAlt tumor model with TGFβ inhibitor, radiation, and/or ICB.
Main Results:
- A high βAlt score predicts ICB response despite association with an immune-poor microenvironment.
- TGFβ inhibition combined with radiotherapy converted immune-poor, high βAlt tumors to immune-rich, ICB-responsive tumors.
- TGFβ inhibition increased activated natural killer (NK) cells, crucial for lymphocyte recruitment and ICB response in irradiated tumors.
Conclusions:
- Loss of TGFβ signaling and gain of error-prone DNA repair identify a subset of cold tumors responsive to ICB.
- Inhibiting TGFβ converts high βAlt cold tumors to ICB-responsive tumors through NK cell activation.
- A combined biomarker signature can identify patients for conversion of cold tumors to hot tumors with targeted therapy.
