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Loretah Chibaya

University of Massachusetts Chan Medical School

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Marcus Ruscetti

University of Massachusetts Chan Medical School

Katherine Murphy

Dana-Farber Cancer Institute

Kelly D. DeMarco

University of Massachusetts Chan Medical School

Lihua Julie Zhu

University of Massachusetts Chan Medical School

Chaitanya N. Parikh

University of Massachusetts Chan Medical School

Griffin Kane

University of Massachusetts Amherst

Wei Luan

Memorial Sloan Kettering Cancer Center

Elisa de Stanchina

Memorial Sloan Kettering Cancer Center

Amanda Kulick

Memorial Sloan Kettering Cancer Center

Yu-Jui Ho

Memorial Sloan Kettering Cancer Center

Cooperative Institutions

University of Massachusetts Chan Medical School

Memorial Sloan Kettering Cancer Center

Kettering University

University of Massachusetts Amherst

Massachusetts Institute of Technology

Harvard University

Amherst College

Spanish National Cancer Research Centre

University of North Carolina at Chapel Hill

Howard Hughes Medical Institute

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EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Loretah Chibaya Katherine Murphy Yvette Lopez-Diaz Kelly D. DeMarco Haibo Liu

ABSTRACT T cell-activating immunotherapies that produce durable and even curative responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be an effective approach to activate not only T cell but also cytotoxic Natural Killer (NK) cell-mediated anti-tumor immunity. Here we found that the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity stimulated the production of pro-inflammatory SASP chemokines CCL2 and CXCL9/10 that led to enhanced NK and T cell infiltration and tumor eradication in preclinical PDAC mouse models. EZH2 activity was also associated with suppression of SASP-associated inflammatory chemokines and cytotoxic lymphocyte immunity and reduced overall survival in a PDAC patient cohort. These results demonstrate that EZH2 mediates epigenetic repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to potentiate NK and T cell surveillance in PDAC to achieve immune-mediated tumor control.

Senescence

10.1101/2022.06.21.495523

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Citations (3)

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

Nature Cancer (2023)

Loretah Chibaya Katherine Murphy Kelly D. DeMarco Sneha Gopalan Haibo Liu

Proinflammatory cytokine

Senescence

10.1038/s43018-023-00553-8

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Citations (55)

Abstract 4043: Nanoparticle-mediated combination therapy to synergistically harness Type I interferons and senescence in the pancreatic tumor microenvironment

Cancer Research (2024)

Prabhani U. Atukorale Marcus Ruscetti Loretah Chibaya Christina F. Lusi Kelly D. DeMarco

Abstract We seek to combine a unique innate immunomodulatory nanoparticle (NP) system with RAS inhibitors for a multi-faceted therapy that mitigates the formidable drug delivery challenges in pancreatic ductal adenocarcinoma (PDAC). PDAC has quickly risen to the third most deadly cancer largely due to its fibrotic, desmoplastic, and immunosuppressive tumor microenvironment (TME) that limits delivery and efficacy of chemo- and immunotherapeutics. We have engineered unique lipid-based NPs that co-encapsulate agonists of the Stimulator of Interferon Genes (STING) and Toll-like Receptor 4 (TLR4) pathways. NPs can be safely delivered in the systemic blood circulation to achieve TME deposition, uptake by innate antigen-presenting cells (APCs), and robust, synergistic production of Type I interferons by dual STING/TLR4 activation. Here, we hypothesize that combination therapy of proinflammatory NPs with tumor senescence-inducing RAS inhibitors, tremetinib and palbociclib, will not only augment CD8+ T cell recruitment to the TME but enhance their sustained activation by mitigating local immunosuppression. In mice bearing orthotopic transplant KPC tumors or KPC GEMMs, combination NP/inhibitor treatment promoted significant NP delivery to tumors, APC and natural killer (NK) cell activation, and CD8+ T cell-mediated clearance, compared to monotherapies and untreated controls. Unexpectedly and strikingly, these studies also showed that, besides innate immune cells, combination therapy also promoted Type I interferon and other proinflammatory cytokine production by PDAC tumor cells, which are otherwise notoriously unresponsive to current state-of-the-art treatments. Further, in KPC GEMMs, 25% of mice exhibited apparent complete responses following combination treatment, which, to our knowledge, is challenging to achieve in this model. Current studies include the mechanistic elucidation of immune- and tumor-intrinsic factors that govern efficacy of our combination therapy. In conclusion, these findings strongly corroborate the use of this NP-based system as a platform therapy for similar drugs and across other aggressive cancers. They also strongly make the case for the rational design of combination therapies to achieve synergistic therapeutic outcomes with minimal systemic toxicities. Citation Format: Prabhani Atukorale, Marcus Ruscetti, Loretah Chibaya, Christina Lusi, Kelly DeMarco, Griffin Kane, Meghan Brassil, Chaitanya Parikh, Katherine Murphy. Nanoparticle-mediated combination therapy to synergistically harness Type I interferons and senescence in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4043.

Pancreatic tumor

Combination therapy

Senescence

10.1158/1538-7445.am2024-4043

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Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Loretah Chibaya Christina F. Lusi Kelly D. DeMarco Griffin Kane Meghan L. Brassil

Pancreatic ductal adenocarcinoma has quickly risen to become the 3

Senescence

10.1101/2023.09.18.558307

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Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer

Science Translational Medicine (2024)

Loretah Chibaya Kelly D. DeMarco Christina F. Lusi Griffin Kane Meghan L. Brassil

Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell–driven and type I interferon–mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8 + T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon–driven innate and adaptive immune response with durable antitumor efficacy against PDAC.

Cancer Immunotherapy

10.1126/scitranslmed.adj9366

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Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis

Proceedings of the National Academy of Sciences (2021)

Loretah Chibaya Baktiar Karim Hong Zhang Stephen N. Jones

We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling and alters the effects of DNA damage in mice, including bone marrow failure and tumorigenesis induced by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage effector kinase. Surprisingly, Akt phosphorylation of Mdm2 does not alter the p53-mediated effects of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 serine residue 183 increases nuclear Mdm2 stability, decreases p53 levels, and prevents senescence in primary cells exposed to reactive oxidative species (ROS). Using multiple mouse models of ROS-induced cancer, we show that Mdm2 phosphorylation by Akt reduces senescence to promote KrasG12D-driven lung cancers and carcinogen-induced papilloma and hepatocellular carcinomas. Collectively, we document a unique physiologic role for Akt-Mdm2-p53 signaling in regulating cell growth and tumorigenesis in response to oxidative stress.

10.1073/pnas.2003193118

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Citations (104)

Abstract A23: Mdm2 phosphorylation by Akt is critical for modulating cellular responses to oxidative stress

Cancer Research (2018)

Loretah Chibaya Hong Zhang Stephen N. Jones

Abstract The serine/threonine kinase Akt is activated by a myriad of growth signals and promotes cell proliferation, survival, and metabolism. Akt is frequently activated in a wide assortment of human hematologic malignancies and solid tumors. In vitro studies demonstrated that Akt phosphorylates the Mdm2 oncoprotein at ser166 and ser186 (163 and 183 in mice) to promote Mdm2 translocation into the nucleus. This enhances Mdm2-mediated p53 ubiquitination and the subsequent proteasomal-mediated degradation of p53. Wild-type p53 protein is a tumor suppressor that is activated in response to stress signals such as DNA damage, oxidative stress, and aberrant oncogene activation. Activated p53 induces the expression of genes that trigger cell cycle arrest, senescence, and apoptosis. This inhibits the growth of damaged and/or potentially oncogenic cells, underscoring the role of p53 in tumor suppression. However, the role of Akt-mediated phosphorylation of Mdm2 on p53 functions in vivo remains unknown. We hypothesize that Mdm2 phosphorylation by Akt at ser183 promotes cell growth and tumorigenesis by reducing p53 levels and function in vivo. Using CRISPR/Cas9-mediated gene editing, we generated mice with mutant Mdm2 protein that cannot be selectively phosphorylated at ser183, by substituting this serine with an alanine. Unlike Mdm2-/- mice that are embryonic lethal, Mdm2S183A mice are viable, fertile, and obtained at Mendelian ratios. There are no apparent growth/weight differences between unchallenged Mdm2WT and Mdm2S183A mice. Other stress-induced kinases like ATM and c-Abl phosphorylate Mdm2 to regulate the levels and functional activity of p53 in response to stress such as DNA damage. In contrast, Akt-mediated phosphorylation of Mdm2 does not alter p53 levels and function in response to DNA damage both in vitro and in vivo. However, under low-density stress plating, the ability of Mdm2S183A MEFs to form colonies is completely abrogated. In addition, Mdm2S183A MEFs fail to proliferate under normal cell culture conditions and exhibit salient features of senescence including positive staining for SA-β Gal. The expression of p53-target genes that mediate senescence is elevated in Mdm2S183A MEFs than in Mdm2WT MEFs. The severe proliferation defect and premature senescent phenotypes observed in Mdm2S183A MEFs are rescued by culturing cells at low oxygen tension with media supplemented with N-acetyl cysteine, a reactive oxygen species (ROS) scavenger. Our results from various assays examining the levels and effects of ROS suggest that under normal cell culture conditions, Mdm2S183A MEFs are more sensitive to oxidative stress compared to Mdm2WT MEFs. So far, our data suggest that Mdm2 phosphorylation by Akt at ser183 is required for proper regulation of the oxidative stress response and is necessary to promote cell growth under normal plating stress conditions. We are currently analyzing RNA-seq data to determine whether there are certain gene expression changes that could aid our quest to decipher the underlying mechanism responsible for the senescent phenotype of Mdm2S183A MEFs. In addition, we have crossed Mdm2S183A to lung and liver cancer models in which ROS plays a pivotal role to examine whether blocking Mdm2 phosphorylation by Akt alters the incidence and progression of tumors. Citation Format: Loretah Chibaya, Hong Zhang, Stephen N. Jones. Mdm2 phosphorylation by Akt is critical for modulating cellular responses to oxidative stress [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A23.

10.1158/1538-7445.mousemodels17-a23

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Abstract B035: Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer

Cancer Research (2024)

Kelly D. DeMarco Loretah Chibaya Christina F. Lusi Griffin Kane Meghan L. Brassil

Abstract Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer- related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-mediated tumor regressions and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated Type I interferon-driven innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC. Citation Format: Kelly D DeMarco, Loretah Chibaya, Christina F Lusi, Griffin I Kane, Meghan L Brassil, Chaitanya N Parikh, Katherine C Murphy, Shreya R Chowdury, Junhui Li, Boyang Ma, Tiana E Taylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R Pitarresi, Lihua Julie Zhu, Katherine A Fitzgerald, Prabhani U Atukorale, Marcus Ruscetti. Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B035.

Senescence

10.1158/1538-7445.pancreatic24-b035

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Abstract PO-124: EZH2 blockade overcomes suppression of the proinflammatory senescence-associated secretory phenotype in the pancreas and drives NK cell-mediated pancreatic tumor responses

Cancer Research (2021)

Loretah Chibaya Yvette Lopez-Diaz Haibo Liu Katherine Murphy John P. Morris

Abstract T cell-targeting immunotherapies that produce durable and sometimes curative responses in other malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to poor T cell infiltration and tumor immunogenicity. We and others have demonstrated that cellular senescence and its associated secretory phenotype (SASP), which leads to production of proinflammatory cytokines, chemokines, and growth factors, can be a powerful way to reactivate a different type of Natural Killer (NK) cell immunity. Recently, we found that RAS pathway targeting MEK and CDK4/6 inhibitors can induce senescence in KRAS mutant lung tumor and PDAC models; however, therapy-induced senescence (TIS) led to NK cell-mediated tumor regressions only in the lungs. Here we set out to understand how the pancreas tumor microenvironment (TME) suppresses NK immunity and develop strategies to harness NK cell surveillance for PDAC immunotherapy. Syngeneic murine KRAS-driven lung tumor and PDAC cells were transplanted into lungs, pancreas, or liver of C57BL/6 mice. Following 2-week treatment with the MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib (T/P) to induce senescence, immune responses were assessed by flow cytometry, and the SASP profile assessed by RNA- and ATAC-seq analysis. An NK1.1-targeted antibody was also used to deplete NK cells and evaluate treatment efficacy. shRNA-mediated EZH2 knockdown and treatment with EZH2 methyltransferase inhibitors in murine and human PDAC cells and mouse models was used to determine the role of EZH2 in SASP regulation by qPCR and cytokine array. The effects of EZH2 blockade on NK cell immunity were determined in co-culture migration and cytotoxicity assays in vitro and in PDAC transplant models in vivo by flow cytometry. The efficacy of T/P treatment in combination with EZH2-targeting shRNAs or inhibitors was measured by ultrasound tumor measurements and survival in PDAC-bearing animals. Tumors propagated in the pancreas TME display transcriptional repression and reduced chromatin accessibility of SASP transcriptional activators (NF-KB, IRFs) and factors necessary for NK cell activity (IL-15,-18) and chemotaxis (CCL2,-7,-8; CXCL9,-10) following TIS, and do not undergo anti-tumor NK immune surveillance as compared to tumors grown in the lungs and liver. We identified induction of EZH2 and repression of its targets, including key SASP factors and regulators, specifically in tumor cells grown in the pancreas TME. Genetic or pharmacological inhibition of EZH2 enhanced proinflammatory SASP signaling and resulted in NK cell infiltration and anti-tumor cytotoxicity in PDAC models. Remarkably, EZH2 knockdown in combination with T/P treatment led to complete tumor regressions in PDAC-bearing mice that were reversed following NK cell depletion. These results demonstrate that EZH2 mediates transcriptional repression of the proinflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with TIS could be a powerful means to reactivate absent NK cell surveillance in PDAC to achieve immune-mediated tumor control. Citation Format: Loretah Chibaya, Yvette Lopez-Diaz, Haibo Liu, Katherine C. Murphy, John P. Morris IV, Yu-jui Ho, Janelle Simon, Wei Luan, Amanda Kulick, Lakhena Leang, Elisa de Stanchina, Lihua J. Zhu, Scott W. Lowe, Marcus Ruscetti. EZH2 blockade overcomes suppression of the proinflammatory senescence-associated secretory phenotype in the pancreas and drives NK cell-mediated pancreatic tumor responses [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-124.

Proinflammatory cytokine

10.1158/1538-7445.panca21-po-124

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Abstract PR005: Modulating the immunosuppressive pancreas tumor microenvironment through intratumoral delivery of cytokine-encoding mRNAs

Molecular Cancer Therapeutics (2024)

Chaitanya N. Parikh Kelly De Marco Boyang Ma Katherine Murphy Loretah Chibaya

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, with a mere 13% average 5-year survival rate. The hallmark desmoplastic stromal response in PDAC leads to poor vascularization, drug delivery challenges, and impaired cytotoxic immune cell infiltration, contributing to de novo therapy resistance. Our previous research has shown therapeutic induction of cellular senescence with RAS pathway targeting therapies can induce cytokine and chemokine production through the senescence-associated secretory phenotype (SASP) that can effectively activate anti-tumor T cell immunity and responses to anti-PD-1 immune checkpoint blockade. To build on these findings as well as overcome limitations associated with senescence-inducing therapy toxicity and induction of pro-tumorigenic SASP cytokines, here we leveraged mRNA technology to deliver specific SASP cytokines and chemokines we have found to stimulate immune responses directly into the suppressive PDAC TME as an immune oncology platform. We created an in vitro transcription pipeline for mRNA production and multiplexing, and demonstrate we can intratumorally deliver multiple mRNAs simultaneously into the TME of transplanted and autochthonous PDAC mouse models, stimulating the local production of cytokines normally absent in PDAC. We further characterized a novel combination of five cytokines and chemokines that can effectively recruit and activate both innate and adaptive immune responses against PDAC. Through repeated bi-weekly dosing, this mRNA combination also promotes tumor destruction and improves survival outcomes. Considering the recent success of off-the-shelf neoantigen mRNA vaccines in early human PDAC patient trials, we have now developed mRNAs that encode PDAC-specific antigens. By integrating our cytokine mRNA platform with antigen mRNAs, we observe a significant increase in intratumoral antigen-presenting dendritic cell populations and a substantially enhanced T-cell mediated anti-tumor immune response in orthotopic transplant models of PDAC. Overall, this study not only unveils pivotal insights into the cytokines absent in PDAC that are crucial for promoting anti-tumor immunity, but also pioneers an innovative immunotherapy approach. This platform has the potential to be integrated with existing immunotherapy modalities, addressing the longstanding challenge of therapy resistance in PDAC. Citation Format: Chaitanya Naimesh Parikh, Kelly De Marco, Boyang Ma, Katherine Murphy, Loretah Chibaya, Lin Zhou, Youwei Qiao, Griffin Kane, Li Li, Wen Xue, Marcus Ruscetti. Modulating the immunosuppressive pancreas tumor microenvironment through intratumoral delivery of cytokine-encoding mRNAs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR005.

10.1158/1538-8514.rnadrivers24-pr005

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