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TNFR1 expression on cancer cell is critical for immunoescape, shaping an immunosuppressive tumor microenvironment [EO771]

ABSTRACT: TNFα reportedly mediates multiple protumor and immunosuppressive functions acting on stromal cells in cancer-bearing hosts as a result of enhancing activation immune cell death of T lymphocytes, causing dysfunction of dendritic cells and/or eliciting chemokines which attract myeloid-derived suppressor cells. Experiments performed in transplantable tumors in which we silenced TNFR1 with CRISPR/Cas9 showed the inability of the TNFR1 KO variants to engraft in immunocompetent hosts, whilst engraftment in immunodeficient or CD8 T lymphocyte-depleted mice was preserved. The mechanism was related to secondary inflammatory mediators elicited by TNFα in malignant cells themselves, including CXCR1/2 chemokines and interestingly TNFα itself. As a result, TNFR1 KO variants recruited drastically fewer myeloid-derived suppressor cells into the tumor microenvironment, thus explaining the immune escape of the WT variants. Interestingly, TNFR1-sufficient tumor cells, when co-engrafted with the TNFR1 KO variants, rescued tumorigenicity of the same tumor lesion but not of a distantly implanted TNFR1 KO tumor. Secondary mediators chiefly include CXCR1/2-acting chemokines and prostaglandin E2 synthetase. Similar effects were observed upon knocking-down TNFR1 in a human tumor cell line. Moreover, human TNFR1 KO HT29 variants, when xenografted in immunodeficient mice, released lower levels of CXCL8 (IL-8) and recruited fewer murine myeloid cells into the tumor microenvironment. Analyses of scRNAseq data sets from human solid tumors corroborate the role of TNFR1 on tumor cells to induce secondary proinflammatory mediators. All together, we provide evidence for an essential role of TNFR1 expressed on the surface of tumor cells in immunoscape and further support TNF neutralization in the clinic to improve the efficacy and safety of approved immunotherapy approaches.

ORGANISM(S): Mus musculus

PROVIDER: GSE309307 | GEO | 2026/08/12

REPOSITORIES: GEO

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Project description:Tumor microenvironment contains abundant quantities of Tumor necrosis factor alpha (TNFα) secreted by a battery of immune cells. Signal flow through TNFα stimulated TNFR1 signaling, which is supposed to maintain a fine balance between survival and cell-death phenotypes, is often sacrificed in a diseased tissue, such as that of a cancer. Strategies to tilt this balance towards cell-death in a tumor that can help improve the therapeutic efficiency are often remain ineffective due to the cell-to-cell variability in expressing different phenotypes. This variability during TNFR1 signaling stems from the heterogeneity in signal flow through intracellular signaling entities that regulate pro-survival and apoptosis responses. This stochastic Boolean dynamic model of TNFR1 signaling focuses on understanding the dynamic cross-talk regulation of apoptosis at single-cell level. We demonstrate with this model that the signal flow path variability can be modulated to enable cells favour apoptosis. We use BM-ProSPR algorithm (GitHub - ganeshIITB/BMProSPR: Codes pertaining to BM-ProSPR) to compute reliable partial state transition graph (pSTG) for the systematic analysis of the dynamical properties of the network at single-cell level (pSTGs of two different conditions are provided as .mat files). Using the pSTG, we derive a comprehensive way to construct ensemble-level dynamics of intracellular signaling entities in order to understand the cross-talk between the pathways (Methods section in manuscript- Time varying conditional probability of finding a node being active). Model analysis juxtaposed with the experimental observations revealed that NFκB and PI3K transient responses guide XIAP to coordinate the crucial dynamic cross-talk between the pro-survival and apoptotic arms at the single-cell level. Model predicted ~31% increase in apoptosis can be achieved by arresting Comp1-IKK* activity. In summary, the analysis of TNFR1 signaling network model provides insights into 1. What are the central regulators for regulating phenotypic response at single-cell level? 2. How do these regulators coordinate the cross-talk between the pathways of different phenotypes? 3. How do the ensemble-level signal flow paths shift towards a phenotype by arresting an entity that regulates the central regulators’ levels?

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TNFR1 expression on cancer cell is critical for immunoescape, shaping an immunosuppressive tumor microenvironment [EO771]

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