Immunotherapy alongside IL-15 promote intratumoral cytotoxic CD4+T cell activation against MHC-II-expressing tumors
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ABSTRACT:
PROVIDER: PRJNA1164327 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30779414_1.fastq.gz | Fastqsanger.gz | |||
| SRR30779414_2.fastq.gz | Fastqsanger.gz | |||
| SRR30779415_1.fastq.gz | Fastqsanger.gz | |||
| SRR30779415_2.fastq.gz | Fastqsanger.gz | |||
| SRR30779416_1.fastq.gz | Fastqsanger.gz |
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Project description:By killing tumor cells, cytotoxic CD8+ T cells are the major effectors in antitumor immunity. A subset of CD4+ T cells also possesses cytotoxic activity by expressing perforin and granzymes and is associated with immunotherapy efficacy. Despite the progress made in characterizing cytotoxic CD4+ T cells in various diseases, the status of cytotoxic CD4+ T cells in non-small cell lung cancer (NSCLC) and the driving mechanisms and forces involved in reviving intratumoral cytotoxic CD4+ T cells remain unclear. Here, we showed that CD4+GzmB+ T cells obtained from patients with NSCLC expressed increased levels of SLC7A5 compared with their counterparts. Upregulation of SLC7A5 was essential for the differentiation of CD4+GzmB+ T cells from naïve CD4+ T cells stimulated with TCR and IL-2. Both T-bet and Eomes are required for the differentiation of CD4+GzmB+ T cells. Interestingly, IL-15 can further increase SLC7A5 expression in differentiated CD4+GzmB+ T cells. Moreover, through activation of the AKT-FOXO1-T-bet axis, IL-15 increased the effector function of intratumoral CD4+GzmB+ T cells. In addition to IL-15, owing to the unique expression profile of PD-1 and CD85j in tumor-infiltrating CD4+GzmB+ T cells, using patient-derived lung cancer explants, we showed that simultaneous blockade of PD-1 and CD85j promoted the effector function of CD4+GzmB+ T cells by activating the AKT pathway. Importantly, using a mouse model of lung cancer, we demonstrated that intrinsic MHC II expression in cancer cells determines the significance of CD4+GzmB+ T-cell-mediated antitumor immunity in response to immunotherapy.
2025-04-09 | GSE277852 | GEO
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.
2014-08-05 | E-GEOD-52171 | biostudies-arrayexpress
Project description:Background: Despite current therapeutic treatments including surgery, chemotherapy, radiotherapy and recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered a dual function of a molecule called QAPHA ((E)-3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)-2-methoxyphenyl)-N-hydroxyacrylamide) as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the lung cancer immune response. Methods: To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterize by flow cytometry. Results In this study, we first show that QAPHA can inhibit HDAC6, leading to upregulation of HSP90, cytochrome C and caspases, found by proteomic analysis. We also confirm that QAPHA induces immunogenic cell death (ICD) by upregulating HMGB1 in vitro and demonstrated its effectiveness as a vaccine in vivo. Remarkably, even at a low concentration (0.5mg/kg), QAPHA achieved complete tumor regression in approximately 60% of intratumorally treated mice, establishing a long-lasting anticancer immune response. Moreover, QAPHA treatment promoted infiltration of neutrophils in the treated mice, reflecting inflammatory cell death promoted. Very interestingly, we show that QAPHA is also able to upregulate MHC-II expression on TC-1 tumor cells in vitro and in vivo. This process participates to the recruitment of CD4+ NKG2D+ CRTAM+ Perforin+ T cells in tumor infiltrate, defined as cytotoxic CD4+ T cells (CD4+ CTL). Finally, we show that tumor regression is strongly correlated to MHC-II expression level on tumor cell and CD4+ CTL infiltrate. Conclusion Collectively, our findings shed light on the discovery of a new multi-target inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate to enhance a specific CD4+ cytotoxic T cell-mediated anti-tumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising therapeutic agent for cancer treatment.
2024-06-16 | PXD042991 | Pride
Project description:Immunotherapy, including immune checkpoint blockade (ICB), has become an effective option for treating patients with cancer, especially those with solid tumors. Recently, T cell-based cellular therapies have extended the scope of immunotherapy to B-cell malignancies. Immunotherapy options for patients with acute myeloid leukemia (AML), however, are limited. To identify new immunotherapy approaches for AML, we performed CRISPR/Cas9 AML T cell co-culture screens. We determined that depletion of the transcription factor IRF2BP2 leads to enhanced T cell killing both in vitro and in vivo. Gene expression profiling and flow cytometry studies confirmed enhanced MHC-I expression upon IRF2BP2 loss. Chromatin binding analysis further revealed a regulatory axis whereby MHC-I expression is repressed by IRF2BP2 through its repression of the interferon alpha pathway. Our studies have identified the inhibition of IRF2BP2 as a potential strategy for enhancing T-cell-based therapies in patients with AML
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2024-12-14 | GSE250160 | GEO
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME.
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Project description:Immune checkpoint inhibitors benefit only a subset of patients, necessitating the development of new sensitizing agents strategies to improve tumor response and efficacy. Major histocompatibility complex class I (MHC-I), vital for tumor antigen presentation and cytotoxic T cell activation, has been an important target of immunotherapy. Nonsense-mediated RNA decay (NMD) is a highly conserved surveillance system that targets mRNAs with premature termination codons (PTCs) and monitors the quantity of about 10% of unmutated mammalian mRNAs. Tumor cells with aneuploidy heavily rely on NMD to compensate the imbalanced DNA levels and lower their antigenicity for immune evasion, making them sensitive to NMD inhibitors. Using an unbiased genome-wide analysis, we unexpectedly identified LTO1/YAE1 complex as novel NMD factors. LTO1/YAE1 complex and its downstream target for iron-sulfur cluster transfer, ABCE1, are widely overexpressed and negatively associated with immune cells infiltration in multiple cancer types. The RNA-sequencing results from these three genes led to the discovery that In tumor cells,compromised NMD is associated with MHC-I upregulation via increased expression of NLRC5, IRF1 and NF-κB in tumor cells. Importantly, we found that low doses of iron chelators, NMD inhibitors in clinical use in treatment of iron overload mimic , enhance MHC-I expression and improvingthese effects and improves immune checkpoint blockade (ICB) efficacy. Our findings suggest that LTO1/YAE1/ABCE1 could be a therapeutic target to enhance cancer immunotherapy by upregulating MHC-I and promoting immune infiltration. Our workfindings links NMD toand iron homeostasis andto the tumor immune microenvironment. Our findings suggest that , highlighting that targeting the NMD could be a therapeutic strategy promote immune infiltration, potentially enhancing cancer immunotherapy.
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Project description:MHC class I (MHC-I)-mediated tumor antigen processing and presentation (APP) pathway is essential for recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we reported that activation of the tumoral intrinsic Hippo pathway positively correlated with the expression of MHC-I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector YAP/TEAD potently improved antitumor immunity. Mechanistically, the YAP/TEAD complex cooperated with the NuRD complex to repress the NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increased the expression of MHC-I APP genes and enhanced CD8+ CTLmediated killing of cancer cells. Collectively, our results suggest a novel tumorpromoting function of YAP depending on NLRC5 to impair MHC-I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.
2024-02-01 | GSE253053 | GEO
Project description:Background: T cell-based immunotherapies including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells can induce durable responses in cancer patients. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of Natural Killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their Major Histocompatibility Complex class I (MHC I) expression due to acquired resistance mechanisms.
However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy.
Method: In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compound on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated utilizing compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types.
Results: The screening approach led to the identification of a Cbl-b inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with TIGIT blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells.
Conclusion: These findings underscore the relevance of Cbl-b inhibition in overcoming NK cells dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for cancer patients.
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