RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer

Wang, Wei; Marinis, Jill M.; Beal, Allison M.; Savadkar, Shivraj; Wu, Yue; Khan, Mohammed Yunus; Taunk, Pardeep S.; Wu, Nan; Su, Wenyu; Wu, Jingjing; Ahsan, Aarif; Kurz, Emma; Chen, Ting; Yaboh, Inedouye; Li, Fēi; Gutierrez, Johana; Diskin, Brian; Hundeyin, Mautin; Reilly, Michael; Lich, John D.; Harris, Philip A.; Mahajan, Mukesh; Thorpe, James H.; Nassau, Pamela M.; Mosley, J.; Leinwand, Joshua; Rossi, Juan Andres Kochen; Mishra, Ankita; Aykut, Berk; Glacken, Michael W.; Ochi, Atsuo; Verma, N. K.; Kim, Jacqueline I.; Vasudevaraja, Varshini; Adeegbe, Dennis O.; Almonte, Christina; Bagdatlioglu, Ece; Cohen, Deirdre Jill; Wong, Kwok-Kin; Bertin, John; Miller, George

doi:10.1016/j.ccell.2018.10.006

Cited by 172 publications

(131 citation statements)

References 63 publications

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“…Whether RIP1 should be targeted in other disease, such as cancer, is less certain. Recent reports have advocated for RIP1 as a target in pancreatic cancer [25,26], but we observed no benefit from inhibiting RIP1 in mouse PDAC. It is important to note that the published studies used invasive procedures for tumor cell implantation.…”

Section: Discussioncontrasting

confidence: 85%

“…3f). Histologic Score NEMO: WT cKO cKO RIP1: WT WT KI We also explored the claim that inhibition of RIP1 reprograms myeloid cells [26]. In contrast to the reported data, we found no evidence that inactivation of RIP1 in macrophages altered gene expression programs or phosphorylation of STAT1 (Fig.…”

Section: Inhibition Of Rip1 Does Not Affect the Growth Of Pancreatic mentioning

confidence: 70%

“…The kinase activity of RIP1 was reported to limit anti-tumor immunity in models of pancreatic ductal adenocarcinoma (PDAC) [25,26]. We examined the role of RIP1 in two different genetically engineered mouse models of PDAC [41].…”

Section: Inhibition Of Rip1 Does Not Affect the Growth Of Pancreatic mentioning

confidence: 99%

“…Recently, the kinase activity of RIP1 was shown to limit anti-tumor immunity in pancreatic cancer models [25,26]. Inhibition of RIP1 suppressed tumor growth by eliciting a highly immunogenic myeloid and T-cell infiltrate [25], due to the reprogramming of tumor-associated macrophages (TAMs) to an M1-like phenotype [26]. Independent studies have claimed that inhibition of RIP1 prevents tumor cell metastasis [27,28].…”

Section: Introductionmentioning

confidence: 99%

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RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

Patel¹,

Webster²,

Varfolomeev³

et al. 2019

Cell Death Differ

101

130

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The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacologically, using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibodyinduced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases.

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Section: Discussioncontrasting

confidence: 85%

Section: Inhibition Of Rip1 Does Not Affect the Growth Of Pancreatic mentioning

confidence: 70%

Section: Inhibition Of Rip1 Does Not Affect the Growth Of Pancreatic mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

Patel¹,

Webster²,

Varfolomeev³

et al. 2019

Cell Death Differ

101

130

View full text Add to dashboard Cite

show abstract

“…Depletion of myeloid cells/macrophages through genetic and pharmacological approaches have demonstrated promising for increasing efficacy of immune checkpoint inhibitors (13,14). Of these myeloid cell populations, tumor-associated macrophages play a relevant role in tumor progression (14), resistance to chemotherapy (15,16), and immune tolerance in PDA (17).…”

Section: Introductionmentioning

confidence: 99%

MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

Filippini

Neander

Delfino

et al. 2019

Preprint

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2The RAF/MEK/ERK (MAP Kinase) pathway is the index oncogenic signaling towards which many 3 compounds have been developed and tested for the treatment of KRAS-driven cancers, including 4 pancreatic ductal adenocarcinoma (PDA). Here, we explored the immunological changes induced 5 by targeted MEK1/2 inhibition (MEKi) using trametinib in preclinical mouse models of PDA. We 6 evaluated the dynamic changes in the immune contexture of mouse PDA upon MEKi using a 7 multidimensional approach (mRNA analyses, flow cytometry, and immunophenotyping). Effect of 8 MEKi on the viability and metabolism of macrophages was investigated in vitro. We showed that 9 transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA 10 subtype (squamous/basal-like/quasimesenchymal), while short term MEKi treatment in mouse 11 PDA induced subtype switching. Integrative mRNA expression and immunophenotypic analyses 12 showed that MEKi reshapes the immune landscape of PDA by depleting rather than 13 reprogramming macrophages, while augmenting infiltration by neutrophils. Depletion of 14 macrophages is observed early in the course of in vivo treatment and is at least partially due to 15 their higher sensitivity to MEKi. Tumor-associated macrophages were consistently reported to 16 interfere with gemcitabine uptake by PDA cells. Here, our in vivo studies show a superior 17 antitumor activity upon combination of MEKi and gemcitabine using a sequential rather than 18 simultaneous dosing protocol. Our results show that MEK inhibition induces a dramatic 19 remodeling of the tumor microenvironment of mouse PDA through depletion of macrophages, 20 which substantially improves the antitumor activity of gemcitabine. 22Pancreatic ductal adenocarcinoma (PDA) has the lowest survival rate of all cancers (1). 25Current therapeutic strategies are mostly based on combination of chemotherapeutic agents, 26 which provides intermittent response and modest survival benefit in the advanced disease setting 27 (2,3). Results from recent clinical trials showed that immune-checkpoint based therapy is rarely 28 active in PDA (4). The complex and heterogenous PDA microenvironment is reported to play a 29 major role in mediating resistance to both chemotherapy and immune therapy (5). In human PDA 30 stromal non-malignant cells often outnumber neoplastic cells, with fibroblasts and macrophages 31 being the dominants cellular components (6). 32Activating mutations of the GTPase KRAS are a nearly universal feature of PDA (7). Activated 33 KRAS engages a multitude of pathways, including the RAF/MEK/ERK (MAP Kinase) pathway, 34 which regulates cellular processes such as proliferation and cell survival (8). Preclinical mouse 35 models show that the oncogenic KRAS-induced cytokine milieu likely contributes to the highly 36 immunosuppressive microenvironment observed already at the preneoplastic PanIN stage (9). In 37 addition to non-cell autonomous effects, KRAS activation and increased activity through the MAP 38Kinase pathway induce cell-intrinsic u...

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Necroptosis‐related regulatory pattern and scoring system for predicting therapeutic efficacy and prognosis in ovarian cancer

Lai,

Guo,

et al. 2023

Cancer Reports

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BackgroundOvarian cancer is difficult to treat and is, therefore, associated with a high fatality rate. Although targeted therapy and immunotherapy have been successfully used clinically to improve the diagnosis and treatment of ovarian cancer, most tumors become drug resistant, and patients experience relapse, meaning that the overall survival rate remains low.AimsThere is currently a lack of effective biomarkers for predicting the prognosis and/or outcomes of patients with ovarian cancer. Therefore, we used published transcriptomic data derived from a large ovarian cancer sample set to establish a molecular subtyping model of the core genes involved in necroptosis in ovarian cancer.Methods and ResultsClustering analysis and differential gene expression analyses were performed to establish the genomic subtypes related to necroptosis and to explore the patterns of regulatory gene expression related to necroptosis in ovarian cancer. A necroptosis scoring system (NSS) was established using principal component analysis according to different regulatory patterns of necroptosis. In addition, this study revealed important biological processes with essential roles in the regulation of ovarian tumorigenesis, including external encapsulating structure organization, leukocyte migration, oxidative phosphorylation, and focal adhesion. Patients with high NSS scores had unique immunophenotypes, such as more abundant M2 macrophages, monocytes, CD4+ memory T cells, and regulatory T cells. Immune checkpoint CD274 had a greater expression in patients with high NSS values.ConclusionThis NSS could be used as an independent predictor of prognosis to determine the sensitivity of ovarian cancer to various small‐molecule inhibitors, immune checkpoint inhibitors, and platinum‐based chemotherapy drugs.

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RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer

Cited by 172 publications

References 63 publications

RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

Necroptosis‐related regulatory pattern and scoring system for predicting therapeutic efficacy and prognosis in ovarian cancer

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