Whole-transcriptome analysis of tumor tissues of lung adenocarcinoma reveals molecular changes under the influence of IFN-γ
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE99995 | GEO | 2020/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
2022-08-08 | E-MTAB-11799 | biostudies-arrayexpress
Project description:Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by anti-tumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor Stat3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathological analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, non-metastatic Stat3-deficient mammary tumors escaped immunosurveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3 inhibitory strategies that may reactivate the immunosurveillance program. We used microarrays to detail determine the transcriptional difference between PyVmT-driven mouse mammary tumors that progressed in the presence or absense of epithelial Stat3. Mammary tumors from transgenic mice were excise and flash frozen. Tumors were analyzed from 8 Stat3-proficient tumors and 6 Stat3-deficient tumors. RNA was extracted and hybridization on Affymetrix microarrays.
2015-11-25 | E-GEOD-75325 | biostudies-arrayexpress
Project description:The elucidation of therapy-induced changes to the class I major histocompatibility complex (MHC-I)-bound tumor antigens is crucial for understanding immune-mediated tumor eradication and identifying potential targets for peptide vaccines to enhance the efficacy of immunotherapies. Here, we investigated how oncolytic reovirus therapy with and without immune checkpoint blockade (ICB) alters the tumor peptide-MHC repertoire. Using mass spectrometry analysis of immunoaffinity purified MHC peptides, we first showed that changes to the MHC immunopeptidome following reovirus treatment is cancer type-dependent, where a murine fibrosarcoma model displayed quantitative and qualitative variance in differentially expressed peptides (DEPs) as compared to those identified in a murine ovarian cancer model. We then determined that the combination therapy of reovirus and ICB in the fibrosarcoma model resulted in higher numbers of DEPs relative to either monotherapy alone. Most importantly, we identified reovirus and ICB-induced MHC peptides that are biologically active in stimulating interferon-gamma response in cognate CD8+ T cells, which likely contribute to cancer immunoediting. These findings highlight the importance of therapy-induced changes to the MHC immunopeptidome in shaping the underlying anti-tumor immune responses during reovirus and ICB combination therapy.
2021-12-06 | PXD024369 | Pride
Project description:Intralesional therapy using Mycobacterium bovis Bacillus Calmette-Guérin (BCG) for cutaneous metastatic melanoma induces regression of injected, but also non-injected lesions. Tumor-associated macrophages (also known as M2) infiltrate solid tumors and impair antitumor immunity. Since macrophages play a pivotal role in both tumors and mycobacterial infections, we hypothesized BCG alters M2 to promote antitumor immunity. BCG-treated, in vitro-polarized M2 (M2-BCG) show dramatic transcriptional changes involving inflammation, immune cell recruitment, cross-talk and activation pathways. Mechanistic network analysis indicates potential for M2-BCG to improve IFN-γ responses, frequently used as a marker for successful antitumor immunity. Accordingly, we found an increased frequency of IFN-γ-producing CD4+ T cells responding to M2-BCG vs mock-treated M2 (p<0.05). Moreover, supernatant from M2-BCG increased the frequency of granzyme B-producing CD8+ tumor-infiltrating lymphocytes (TIL) responding to autologous melanoma cell lines (p<0.01). Comparing the transcriptome of injected vs uninjected lesions biopsied from IL-BCG patients showed immune function prevailing in injected lesions, with the most enriched pathways representing T cell activation mechanisms. In vitro BCG-infected tumor cells also stimulated IFN-γ production from HLA-A2-restricted syngeneic TIL from the same melanoma patient (p<0.05). Together, our data indicates BCG can promote an antitumor microenvironment in cutaneous metastatic melanoma.
2017-09-14 | GSE90748 | GEO
Project description:Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate NK cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 screens. This identified all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitized melanoma, breast and colorectal cancer cells to both NK and CD8+ T cell killing. This occurred in a TNF-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF Receptor Complex I. Corroborating this preclinically, a small molecule RNF31 inhibitor sensitized human colon carcinoma organoids to TNF and greatly enhanced immune bystander killing of antigen-loss and antigen presentation machinery-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers.
2022-05-30 | PXD029489 | Pride
Project description:This is a mathematical model investigating interactions among malignant tumor cells, CD4+ T cells, anti-tumor cytokines (specifically IFN-gamma), and the immune checkpoint inhibitor CTLA-4 to assess the importance of immune checkpoints in mediating tumor regression.
2019-11-27 | MODEL1911270002 | BioModels
Project description:All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) can convey non-self antigens derived from pathogens or mutations to amount T-cell responses. Alterations in tumor-specific antigens – particularly mutation-bearing peptides (neoantigens) presented by MHC — can serve as potent substrates for anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring interferon gamma (IFN-γ) induced alterations to antigen presentation, using a lymphoma cell line. IFN-γ treatment resulted in a set of differentially expressed proteins (2 % of all quantified proteins) including components of antigen presentation machinery or interferon signaling pathways. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells antigen repertoires. Accordingly, by surveying immunopeptides, distinct peptide repertoires were exclusively observed in the IFN-γ induced samples. Furthermore, an additional set of presented peptides distinguished control and the IFN-γ samples by their altered relative abundances including neoantigens. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance should help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.
2021-09-09 | PXD020750 | Pride
Project description:Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or anti-vector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin (IL)-12 single chain, interferon (IFN)-α, granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-γ induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors as well as disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway.
2021-07-10 | GSE179738 | GEO
Project description:This mathematical model describes interactions between glioma tumors and the immune system that may occur following direct intra-tumoral administration of ex-vivo activated alloreactive cytotoxic-T-lymphocytes (aCTLs) as part of adoptive immunotherapy. The model includes descriptions of aCTL, neoplastic cells, MHC class I and II molecules, TGF-beta and IFN-gamma.
2019-09-09 | BIOMD0000000808 | BioModels
Project description:Type I interferons (IFNs) play a central role in innate immunity against virus infection, but also in the antitumour response. In tumour biology, an important mechanism of action apart from the more indirect immune-modulatory and anti-angiogenic effects of IFNs, is their direct impact on cell proliferation. Particularly for cancers arising in the context of chronic inflammation, constant exposure of cells to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of tumour subclones or -populations that developed resistance to the antiproliferative effects of IFN might constitute an important contribution to immunoediting of the tumour leading to more aggressive and metastasising disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that prolonged (six weeks) exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines of varying malignity. IFN-resistance was most prominent in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours, fostering the hypothesis of IFN-driven immunoediting in advanced cancers. In both settings, long-term IFN selection in vitro as well as in dedifferentiated tumour cell lines, we found IFNAR expression to be substantially reduced, suggesting the receptor complex, in particular IFNAR2, to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.
2023-11-21 | PXD043761 | Pride