A conserved subset of cold tumors responsive to immune checkpoint blockade
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PROVIDER: PRJNA1231497 | ENA |
REPOSITORIES: ENA
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Project description: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 concomitant evaluation of 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 converted 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 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
2025-08-20 | GSE291071 | GEO
Project description:BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.
| S-EPMC11887281 | biostudies-literature
Project description:Despite the curative potential of checkpoint blockade immunotherapy, most patients remain unresponsive to existing treatments. Glyco-immune checkpoints – interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors – have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin “decoy receptor” domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate anticancer immune responses including phagocytosis and cytotoxicity, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumor and immune cell subsets as well as glyco-immune checkpoints, and therefore represent a new modality for cancer immunotherapy.
2025-08-13 | PXD063934 | Pride
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100808 | GEO
Project description:An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1? TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.
2019-01-16 | GSE122969 | GEO
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100807 | GEO
Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.
2023-11-08 | PXD039705 | Pride
Project description:Conserved interferon-gamma signaling and decreased immune exclusion programs in responses to immune checkpoint blockade therapy
| PRJNA648116 | ENA
Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.
2023-11-08 | PXD044987 | Pride
Project description:Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study
| PRJNA397812 | ENA