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Therapeutic decoupling of MHC-I and PD-L1 expression increases the efficacy of immune checkpoint blockade (SMAC_RNAseq)

ABSTRACT: Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of multiple cancers, but the majority of patients remain refractory due to impaired MHC-I expression. Although the combination of immunotherapy with existing anti-cancer treatments has shown synergy in multiple scenarios, the immunomodulatory effects of conventional therapies remain poorly understood. Here, we integrated CRISPR-mediated genetic screens and data mining of perturbation associated gene expression data to identify drugs that can specifically up-regulate MHC-I without inducing PD-L1. Using FACS-based genome-wide CRISPR screens, we identified Traf3, a critical suppressor of the NF-κB pathway, as a suppressor of MHC-I, but not PD-L1. A Traf3-knockout gene expression signature is associated with better survival in ICB-naive cancer patients and better response to ICB in published clinical trials. From publicly available drug treatment data, we identified SMAC mimetics as the top candidates of having similar transcriptional effects as Traf3-knockout. We experimentally validated that the SMAC mimetic birinapant specifically up-regulated MHC-I, sensitized cancer cells to T-cell-dependent killing, and synergized with ICB in the treatment of established tumors. Our findings provide a strong preclinical rationale for treating MHC-I-low tumors with SMAC mimetics to enhance sensitivity to existing immunotherapy. Moreover, the integrated approach used in this study can be generalized to identify drugs with immunomodulatory effects to enhance immunotherapy efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE149825 | GEO | 2020/07/01

REPOSITORIES: GEO

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Therapeutic decoupling of MHC-I and PD-L1 expression increases the efficacy of immune checkpoint blockade (koTRAF3_ATACseq)

Project description:Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of multiple cancers, but the majority of patients remain refractory due to impaired MHC-I expression. Although the combination of immunotherapy with existing anti-cancer treatments has shown synergy in multiple scenarios, the immunomodulatory effects of conventional therapies remain poorly understood. Here, we integrated CRISPR-mediated genetic screens and data mining of perturbation associated gene expression data to identify drugs that can specifically up-regulate MHC-I without inducing PD-L1. Using FACS-based genome-wide CRISPR screens, we identified Traf3, a critical suppressor of the NF-κB pathway, as a suppressor of MHC-I, but not PD-L1. A Traf3-knockout gene expression signature is associated with better survival in ICB-naive cancer patients and better response to ICB in published clinical trials. From publicly available drug treatment data, we identified SMAC mimetics as the top candidates of having similar transcriptional effects as Traf3-knockout. We experimentally validated that the SMAC mimetic birinapant specifically up-regulated MHC-I, sensitized cancer cells to T-cell-dependent killing, and synergized with ICB in the treatment of established tumors. Our findings provide a strong preclinical rationale for treating MHC-I-low tumors with SMAC mimetics to enhance sensitivity to existing immunotherapy. Moreover, the integrated approach used in this study can be generalized to identify drugs with immunomodulatory effects to enhance immunotherapy efficacy.

2020-07-01 | GSE149821 | GEO

Therapeutic decoupling of MHC-I and PD-L1 expression increases the efficacy of immune checkpoint blockade (koTRAF3_RNAseq)

2020-07-01 | GSE149824 | GEO

Therapeutic decoupling of MHC-I and PD-L1 expression increases the efficacy of immune checkpoint blockade (CRISPR_Screen)

2020-07-01 | GSE149822 | GEO

Inhibition of MAN2A1 enhances tumor response to anti-PD-L1

Project description:Immune checkpoint blockade (ICB) has shown remarkable efficacy, but in only a minority of cancer patients, suggesting the need to develop additional treatment strategies.We integrated transcriptional profiles of treatment-naïve human tumors and functional CRISPR screens to identify glycometabolism genes with immunomodulatory effects. We identified MAN2A1, encoding an enzyme in N-glycan maturation, as a key immunomodulatory gene. Analyses of public immune checkpoint blockade trial data also suggested a synergy between MAN2A1 inhibition and anti-PD-L1 treatment. Loss of Man2a1 in cancer cells increased their sensitivity to T cell-mediated killing. Man2a1 knockout enhanced response to anti-PD-L1 treatment and facilitated higher cytotoxic T cell infiltration in tumors under anti-PD-L1 treatment. Furthermore, a pharmacological inhibitor of MAN2A1, swainsonine, synergized with anti-PD-L1 in syngeneic melanoma tumor model, whereas each treatment alone had little effect.

2020-08-17 | GSE152925 | GEO

Expression data from MDA-MB-231 parental and xenograft tumor cells treated with Smac mimetic SM-164.

Project description:Small-molecule Smac mimetics target inhibitor of apoptosis (IAP) proteins to induce TNFÎ±-dependent apoptosis in cancer cells and several Smac mimetics have been advanced into clinical development as a new class of anticancer drugs. However, preclinical studies have shown that only a small subset of cancer cell lines are sensitive to Smac mimetics used as single agents and these cell lines are at risk of developing drug resistance to Smac mimetics. Thus, it is important to understand the molecular mechanisms underlying intrinsic and acquired resistance of cancer cells to Smac mimetics in order to develop effective therapeutic strategies to overcome or prevent Smac mimetic resistance. We established Smac mimetic resistant sublines derived from MDA-MB-231 breast cancer cells, which exhibit exquisite sensitivity to the Smac mimetic SM-164, and used microarrays to detail the global programme of gene expression underlying SM-164 resistance in MDA-MB-231 cells and identified differentially expressed genes in SM-164-resistant and -sensitive MDA-MB-231 cells. SCID mice with MDA-MB-231 xenograft tumors were treated with 5 mg/kg of SM-164 intravenously for 5 days/week for 2 weeks. SM-164-regressed MDA-MB-231 tumors regrew after treatment ended. Tumor cells from these regrown MDA-MB-231 tumors were isolated and total RNAs were prepared for microarray analysis.

2012-03-01 | E-GEOD-33827 | biostudies-arrayexpress

Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via Type I interferon pathway in PD-L1+ expressing head and neck cancer

Project description:Immune checkpoint blockers (ICBs) targeting programmed death 1(PD-1) are considered effective first-line therapy against PD-1 ligand (PD-L1)-expressing head and neck squamous cell carcinoma (HNSCC). However, associated changes in tumor microenvironment (TME) and mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou Oral Cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC xenograft model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in TME, including vascular normalization. Furthermore, the anti-tumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and anti-vascular endothelial growth factor receptor 2 inhibitors. The ICB-induced anti-tumorigenicity and TME normalization were alleviated by blocking the Type I interferon pathway.In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the Type-I interferon pathway is indispensable in realizing ICB effects. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against HNSCC expressing PD-L1 in the KEYNOTE-048 trial. This model can assist future research on HNSCC immunotherapy.

2023-12-01 | GSE248271 | GEO

Expression data from MDA-MB-231 parental and xenograft tumor cells treated with Smac mimetic SM-164.

Project description:Small-molecule Smac mimetics target inhibitor of apoptosis (IAP) proteins to induce TNFα-dependent apoptosis in cancer cells and several Smac mimetics have been advanced into clinical development as a new class of anticancer drugs. However, preclinical studies have shown that only a small subset of cancer cell lines are sensitive to Smac mimetics used as single agents and these cell lines are at risk of developing drug resistance to Smac mimetics. Thus, it is important to understand the molecular mechanisms underlying intrinsic and acquired resistance of cancer cells to Smac mimetics in order to develop effective therapeutic strategies to overcome or prevent Smac mimetic resistance. We established Smac mimetic resistant sublines derived from MDA-MB-231 breast cancer cells, which exhibit exquisite sensitivity to the Smac mimetic SM-164, and used microarrays to detail the global programme of gene expression underlying SM-164 resistance in MDA-MB-231 cells and identified differentially expressed genes in SM-164-resistant and -sensitive MDA-MB-231 cells.

2012-03-01 | GSE33827 | GEO

Comprehensive testing of chemotherapy and immune checkpoint blockade in preclinical cancer models identifies additive combinations

Project description:Background: Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA 4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. Methods: We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. Results: 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8+ T cell activation and upregulation of IFN , TNF and IL-1β signaling. The effective anti tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8+ T cells but was unaffected when TNF or IL 1β cytokine signaling pathways were blocked. Conclusions: Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.

2022-05-02 | GSE188481 | GEO

Gene Expression profile for the characterization of PD-L1 blockade in melanoma model

Project description:Only a subset of patients responds to immune checkpoint blockade in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti-mouse PD-L1 antibody similar to the anti-human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T cell infiltration, and T cell receptor (TCR) signatures in regressing tumors compared to tumors exhibiting no response to anti-PD-L1 treatment. We found that CD8+ T cell tumor infiltration corresponded to response to treatment, and that anti-PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine-cytokine receptor interaction, and natural killer cell-mediated cytotoxicity. TCR sequence data suggest that an anti-PD-L1-mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy.

2021-04-20 | GSE172320 | GEO

Gene Expression profile for the characterization of PD-L1 blockade in melanoma model

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