Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PIKfyve inhibition upregulates surface expression of MHC class I to enhance immune responses in cancer

ABSTRACT: Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit primary resistance. Here, we found thatgenetic or pharmacologic inhibitionof the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis,upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, reduced tumor proliferation, and increased intratumoral functional CD8+T cellsinsyngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion was CD8+T cell- and MHC-I-dependent,as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to various immunotherapies, including immune checkpoint blockade (ICB), adoptive cell therapy, and therapeutic vaccines. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as novel agents to increase immunotherapy response in cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE235945 | GEO | 2023/11/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Mapping of immunopeptidome of cancer immunotherapy with oncolytic virus and checkpoint blockade

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

Activated SUMOylation restricts the MHC class I antigen presentation pathway to confer immune evasion in cancer

Project description:Activated SUMOylation is a hallmark of aggressive cancers. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionary conserved function of activated SUMOylation, which attenuates the immunogenicity of tumor cells. Activated SUMOylation allows cancer cells to evade CD8+ T-cell immunosurveillance by repressing the MHC-I antigen processing and presentation machinery (APM). While loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, the pharmacological inhibition of SUMOylation (SUMOi) restored the expression of the MHC-I APM and enhanced the susceptibility of tumor cells to CD8+ T-cell mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T-cells itself and thereby drives a feed-forward loop amplifying the specific anti-tumor immune response. In summary, we show that activated SUMOylation converts tumor cells into a state of immune evasion, and identify SUMOi as rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.

2022-01-15 | PXD030506 | Pride

Rebalancing TGFβ1/BMP Signals Preserves Effector and Memory Programs in Terminally Dysfunctional CD8+ T Cells [Bisulfite-Seq]

Project description:T cell dysfunctionality prevents clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits durable responses to T cell-based immunotherapies, including immune checkpoint blockade (ICB). However, major gaps concern how upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here, we use an in vitro model of human T cell dysfunction and complementary in vivo mouse chronic virus infection and tumor models. We show that post-effector TGFβ1 signaling establishes terminal dysfunction in human CD8+ T cells through stable epigenetic changes. Importantly, we demonstrate that promoting BMP signaling while blocking TGFβ1 restored effector and memory programs in dysfunctional human CD8+ T cells, induced superior anti-tumor activity, and boosted ICB responses during mouse chronic virus infection. Thus, rebalancing TGFβ1/BMP-signals in dysfunctional CD8+ T cells provides an exciting new approach to enhance T cell immunotherapies.

2022-11-03 | GSE217087 | GEO

Rebalancing TGFβ1/BMP Signals Preserves Effector and Memory Programs in Terminally Dysfunctional CD8+ T Cells [RNA-Seq]

2022-11-03 | GSE217072 | GEO

A ketogenic diet can revert acquired resistance to immunotherapy in prostate cancer through β-hydroxybutyrate-mediated inhibition of histone deacetylases

Project description:Prostate cancer is the second leading cause of cancer deaths in men in the US. In the past decade, immune checkpoint blockade (ICB) drugs targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have revolutionized the field of cancer therapeutics, but the objective response rate in prostate cancers is in the low single digits. A major complicating issue is that immunotherapies can have significant adverse effects, so there is a clinical need for novel combinatorial strategies that do not involve additional or compounding adverse effects. We developed a model system of advanced prostate cancer that has acquired resistance to ICB therapy. The PD-1 resistant sublines showed strong downregulation of the mouse major histocompatibility complex (MHC-I), which was reversed by treating cells with either the pan-histone deacetylase (HDAC) inhibitor Vorinostat or β-hydroxybutyrate. When mice bearing these ICB resistant tumor are treated with either Vorinostat, with a cyclical ketogenic diet (CKD), or with a 1,3-butanediol diet (BD), tumors are resensitized to ICB therapy. We analyzed changes in the tumor immune microenvironment and showed that this effect is driven by a shift in monocyte differentiation, changing from M2 polarized immunosuppressive macrophages into iNOS+ dendritic cells instead. This differentiation is dependent on an ICB-induced increase in CD40L+ CD8+ T-cells in the tumor immune microenvironment. Our results indicate a novel mechanism in which a ketogenic diet can be used to increase therapeutic efficacy of ICB therapy.

2024-02-13 | GSE206561 | GEO

Integrative MHC-I peptidome quantitation with isobaric tagging mass spectrometry

Project description:Despite the appreciation of CD8+ T cell anti-tumor immune responses towards improvement patient outcomes, the MHC-I peptides that facilitate the response are poorly described. Alternatively, whether cancer therapies alter the MHC-I peptide repertoire has not been fully assessed due to the lack of quantitative strategies. In this regard, anthracyclines and ionizing radiation both increase the infiltration of CD8+ T cells into tumors but whether they do so by altering the MHC-I peptidome repertoire is not known. To investigate this, we developed a platform for screening therapy-induced MHC-I peptides by quantitative, multiplexed measurement of MHC-I peptides with tandem mass tags (TMT). We show that both ionizing radiation and the anthracycline doxorubicin induce MHC-I peptides that are largely derived from mitotic progression and cell cycle proteins. Our approach enables further strategies to understand how small molecules and other therapies alter MHC-I peptide presentation that may be harnessed for CD8+ T cell-based immunotherapies.

2019-03-05 | PXD011464 | Pride

Integrative MHC-I peptidome quantitation with isobaric tagging mass spectrometry

2019-03-05 | PXD011444 | Pride

RNA-seq analyses of autophagy-high and autophagy-low cells from human colon cancer organoids

Project description:We isolated the human colon cancer cells expressing high leveles and low levels of autophagic activity by introdicing an autophagic flux indicator in organoids and performed RNA-seq analyses.

2023-04-23 | GSE193936 | GEO

CD4+ T-cell-induced inflammatory killing controls immune evasive tumors

Project description:Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T-cells to directly recognise and kill tumor cells. These strategies are limited by the emergence of MHC-deficient tumor cells and the development of an immunosuppressive tumor microenvironment. The ability of CD4+ effector cells to contribute to anti-tumor immunity independently of CD8+ T-cells is increasingly recognised, but strategies to unleash their full potential remain to be identified. Here, we describe a mechanism through which a small number of CD4+ T-cells is sufficient to eradicate MHC-deficient tumors that escape direct CD8+ T-cell targeting. The CD4+ effector T-cells preferentially cluster at tumor invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that Th1-directed CD4+ T-cells and innate immune stimulation reprogram the tumor-associated myeloid cell network towards IFN-activated antigen-presenting and iNOS-expressing tumoricidal effector phenotypes. Together, CD4+ T-cells and tumoricidal myeloid cells orchestrate a remote inflammatory cell death process that indirectly eradicates IFN-unresponsive and MHC-deficient tumors. These results warrant to clinically exploit the ability of CD4+ T-cells and innate immune stimulators as a strategy to complement the direct cytolytic activity of CD8+ T- and NK-cells and advance cancer immunotherapies.

2023-05-24 | GSE230427 | GEO

Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens

Project description:The success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented on MHC-I molecules. We demonstrated that the splicing inhibitor isoginkgetin and its water-soluble and non-toxic derivative IP2 act at the production stage of the Pioneer Translation Products (PTPs). We showed that IP2 increases PTP-derived antigen presentation in cancer cells in vitro and impairs tumor growth in vivo. IP2 action is long-lasting and dependent on the CD8+ T cell response against TAs. We observed that the antigen repertoire displayed on MHC-I molecules at the surface of MCA205 fibrosarcoma is modified upon treatment with IP2. In particular, IP2 enhances the presentation of an exon-derived epitope from the tumor suppressor nischarin. The combination of IP2 with a peptide vaccine targeting the nischarin-derived epitope showed a synergistic antitumor effect. These findings identify the spliceosome as a druggable target for the development of epitope-based immunotherapies.

2021-03-02 | PXD023019 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data