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Landscape of immune checkpoint blockade-induced immune alterations in the microenvironment of primary and metastatic brain tumors

ABSTRACT: Landscape of immune checkpoint blockade-induced immune alterations in the microenvironment of primary and metastatic brain tumors

PROVIDER: PRJNA797449 | ENA |

REPOSITORIES: ENA

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Landscape of immune checkpoint blockade-induced immune alterations in the microenvironment of primary and metastatic brain tumors

Project description:Brain tumors reside in an immune privileged microenvironment where inflammatory processes are heavily regulated. Nevertheless, our recent study showed a significant immune infiltration in recurrent glioblastoma (rGBM) treated with neoadjuvant PD-1 checkpoint blockade therapy. Compared to GBM, the intracranial immunotherapy response of brain metastases (BrM) has been much less studied. Therefore we studied the effect of pre-surgical immune checkpoint blockade (ICB) on the immune compartments of BrM, using multiplex immunofluorescence, mass cytometry and single-cell RNA sequencing. ICB induced much higher T cell infiltration in BrM compared to rGBM. It also caused the loss of a unique perivascular macrophage subset (CD206+LYVE1+), the absence of which associated with the enhanced T cell infiltration in BrM. These T cells produced high levels of IFN-γ that elicited and interferon response transcriptional program in the tumor-associated myeloid cells. T cell-myeloid interactions were also strengthened by ICB in BrM and might have led to the terminal exhaustion of the infiltrating T cells. Our results emphasize the importance of adopting novel immune-boosting approaches to rejuvenate the systemic T cell pool so as to improve tumor control of brain metastases.

2023-07-06 | GSE193745 | GEO

Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer

Project description:Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer

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Concurrent delivery of immune checkpoint blockade improves tumor microenvironment for vaccine-generated immunity

Project description:Concurrent delivery of immune checkpoint blockade improves tumor microenvironment for vaccine-generated immunity

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Chemohormonal Therapy Remodels Prostate Cancer Immune Microenvironment and Enhances Checkpoint Inhibitor-based immunotherapy

Project description:Checkpoint blockade immunotherapy is a promising strategy in cancer treatment, depending on a favorable preexisting tumor immune microenvironment. However, prostate cancer is usually considered as an immune “cold” tumor with the poor immunogenic response and low density of tumor-infiltrating immune cells. This research uses samples from prostate cancer patients showing that docetaxel-based chemohormonal therapy reprograms the immune microenvironment and increases tumor-infiltrating T cells. Mechanistically, docetaxel treatment activates the cGAS/STING pathway and induces the type I interferon signaling, which may boost T cell-mediated immune response. In a murine prostate cancer model, chemohormonal therapy sensitizes tumor-bearing mice to PD1-blockade therapy. These findings demonstrate that docetaxel-based chemohormonal therapy activates prostate cancer immunogenicity and acts cooperatively with anti-PD-1 checkpoint blockade, providing a combination immunotherapy strategy that would lead to better therapeutic benefit for prostate cancer.

2022-08-01 | GSE193898 | GEO

Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [tumor]

Project description:Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [tumor]

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Single cell transcriptomics of the tumor immune microenvironment from checkpoint blockade-treated KPC tumors

Project description:Single cell transcriptomics of the tumor immune microenvironment from checkpoint blockade-treated KPC tumors

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Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade

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

Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

Project description:Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

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Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

Project description:Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

| PRJNA397812 | ENA

Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade (part 2)

2023-11-08 | PXD044987 | Pride