Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS

Kitajima, Shunsuke; Asahina, Hajime; Chen, Ting; Guo, Sujuan; Quiceno, Laura Gutierrez; Cavanaugh, Jillian D.; Merlino, Ashley A.; Tange, Shoichiro; Terai, Hideki; Kim, Jong Wook; Wang, Xiaoen; Zhou, Shan; Xu, Man; Wang, Stephen; Zhu, Zehua; Thai, Tran C.; Takahashi, Chiaki; Wang, Yujin; Neve, Richard M.; Stinson, Susanna; Tamayo, Pablo; Watanabe, Hideo; Kirschmeier, Paul T.; Wong, Kwok-Kin; Barbie, David A.

doi:10.1016/j.ccell.2018.08.009

Cited by 51 publications

(46 citation statements)

References 47 publications

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“…Similarly, poly(dA:dT) transfection of cancer cells followed by spheroid formation and microfluidic 3-D culture revealed that LKB1-reconstituted 3-D spheroids uniquely responded to transfection of cytoplasmic DNA, significantly upregulating multiple immune cell chemoattractants including CCL5, CCL2, and CXCL10, after 7 days ( Figures 1D,E and Supplementary Figure S1B ). Notably, IL-6 was suppressed by LKB1 reconstitution as previously described ( 24 , 25 ) ( Figure 1E and Supplementary Figure S1B ). In contrast, control MVNs expressed high levels of CCL2 and IL-8, as well as IL-6 ( Supplementary Figures S1C,D ).…”

Section: Resultssupporting

confidence: 75%

Tumor-Derived cGAMP Regulates Activation of the Vasculature

et al. 2020

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Intratumoral recruitment of immune cells following innate immune activation is critical for anti-tumor immunity and involves cytosolic dsDNA sensing by the cGAS/STING pathway. We have previously shown that KRAS-LKB1 (KL) mutant lung cancer, which is resistant to PD-1 blockade, exhibits silencing of STING, impaired tumor cell production of immune chemoattractants, and T cell exclusion. Since the vasculature is also a critical gatekeeper of immune cell infiltration into tumors, we developed a novel microfluidic model to study KL tumor-vascular interactions. Notably, dsDNA priming of LKB1reconstituted tumor cells activates the microvasculature, even when tumor cell STING is deleted. cGAS-driven extracellular export of 2 3 cGAMP by cancer cells activates STING signaling in endothelial cells and cooperates with type 1 interferon to increase vascular permeability and expression of E selectin, VCAM-1, and ICAM-1 and T cell adhesion to the endothelium. Thus, tumor cell cGAS-STING signaling not only produces T cell chemoattractants, but also primes tumor vasculature for immune cell escape.

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Section: Resultssupporting

confidence: 75%

Tumor-Derived cGAMP Regulates Activation of the Vasculature

et al. 2020

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“…Since both IRF3 and downstream STAT1 signaling have anti-viral cytotoxic functions, we co-treated cells with Compound 1 (TBK1i) or the JAK/STAT inhibitor Ruxolitinib (Ruxo) to assess the relative contributions of these pathways to STING mediated apoptosis. Whereas TBK1 inhibition itself impaired viability of KL cells (14) yet partially reversed STING cytotoxicity, Ruxo mediated pSTAT1 inhibition strongly rescued STING-induced cell growth arrest and apoptosis (Fig. 4E, F, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 94%

“…In the absence of STING or activation of other viral sensors such as MAVS, TBK1 fails to bridge with IRF3 (16), favoring NF-κB associated induction of alternate cytokines such as IL-6 that instead promote cell survival and myeloid cell recruitment (1,9). Indeed, TBK1 and IKKε mediated pro-tumorigenic cytokine circuits are known to contribute to tumor progression in KRAS mutant lung cancers, involving IL-6-STAT3 activation (9,14). Importantly, epigenetic silencing of DNA sensing was restricted to STING expression, as KL cells maintained cGAS.…”

Section: Discussionmentioning

confidence: 99%

Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer

et al. 2019

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KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL) mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS mutant lung cancers, remains obscure. Here we report that LKB1 loss results in marked silencing of STING expression and insensitivity to cytoplasmic double strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine (SAM) levels, and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape.

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“…Indeed, addition of the LKB1 mutation to KRAS mutant NSCLC cells is significantly correlated with the aberrant accumulation of cytoplasmic mitochondrial DNA and higher mitochondrial ROS production [113]. Similar to RB-depleted cells that exhibit higher pro-inflammatory cytokines production due to increased mitochondrial ROS, KRAS;LKB1-mutated NSCLC cells highly produce cytokines, such as IL-6 and CCL5 [114,115]. Higher secretion of these pro-inflammatory cytokines not only promotes cell growth and cell survival in a cell-autonomous manner but also contributes to the formation of immunosuppressive TME in a non-cell-autonomous manner [114,115].…”

Section: Role Of Other Tumor Suppressor Proteins In the Tmementioning

confidence: 99%

“…Similar to RB-depleted cells that exhibit higher pro-inflammatory cytokines production due to increased mitochondrial ROS, KRAS;LKB1-mutated NSCLC cells highly produce cytokines, such as IL-6 and CCL5 [114,115]. Higher secretion of these pro-inflammatory cytokines not only promotes cell growth and cell survival in a cell-autonomous manner but also contributes to the formation of immunosuppressive TME in a non-cell-autonomous manner [114,115]. On the other hand, aberrant accumulation of cytoplasmic DNA derived from mitochondria in KRAS;LKB1-mutated NSCLC cells stimulates the cGAS-STING pathway, as discussed above.…”

Section: Role Of Other Tumor Suppressor Proteins In the Tmementioning

confidence: 99%

Tumor Milieu Controlled by RB Tumor Suppressor

Kitajima

Takahashi

2020

IJMS

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The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of the RB gene is most commonly detected in tumors when they gain more aggressive phenotypes, including metastatic activity or drug resistance, rather than accelerated proliferation. This implicates RB controls’ malignant progression to a considerable extent in a cell cycle-independent manner. In this review, we highlight the multifaceted functions of the RB protein in controlling tumor lineage plasticity, metabolism, and the tumor microenvironment (TME), with a focus on the mechanism whereby RB controls the TME. In brief, RB inactivation in several types of cancer cells enhances production of pro-inflammatory cytokines, including CCL2, through upregulation of mitochondrial reactive oxygen species (ROS) production. These factors not only accelerate the growth of cancer cells in a cell-autonomous manner, but also stimulate non-malignant cells in the TME to generate a pro-tumorigenic niche in a non-cell-autonomous manner. Here, we discuss the biological and pathological significance of the non-cell-autonomous functions of RB and attempt to predict their potential clinical relevance to cancer immunotherapy.

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Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS

Cited by 51 publications

References 47 publications

Tumor-Derived cGAMP Regulates Activation of the Vasculature

Tumor-Derived cGAMP Regulates Activation of the Vasculature

Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer

Tumor Milieu Controlled by RB Tumor Suppressor

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