MEK Inhibition Remodels the Immune Landscape of Mutant <i>KRAS</i> Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors

Yang, Bin; Li, Xi; Fu, Yu; Guo, Ensong; Ye, Youqiong; Li, Fuxia; Liu, Si; Xiao, Rourou; Liu, Chen; Lü, Fang; Huang, Jia; Qin, Tianyu; Han, Leng; Peng, Guang; Mills, Gordon B.; Sun, Chaoyang; Chen, Gang

doi:10.1158/0008-5472.can-20-2370

Cited by 34 publications

(28 citation statements)

References 50 publications

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“…1l, m ). Further, gene set enrichment analysis (GSEA) of signatures or signaling pathways associated with M2-like macrophage polarization or an immunosuppressive TIME 32 , 33 , such as epithelial mesenchymal transition (EMT), STAT3 targets, angiogenesis, hypoxia, TGF-beta signaling, and KRAS signaling, were upregulated in BRCA1 -mutant breast tumors compared to BRCA1 -mutant ovarian tumors (Supplementary Fig. 1n, o ).…”

Section: Resultsmentioning

confidence: 99%

STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

et al. 2022

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PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.

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Section: Resultsmentioning

confidence: 99%

STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

et al. 2022

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“… 60 A recent study reported that inhibitors of MEK and PARP induce DNA damage and STING signaling in KRAS mutant cells but not A549 cells. 61 In our study, we used A549 cells, which harbor mutations in KRAS and LKB1. As expected, we found that STING expression in A549 cells was much lower than that in HCC827 cells.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ activates the tumor cell-intrinsic STING pathway through the induction of DNA damage and cytosolic dsDNA formation

Xiong

Yuan

et al. 2022

OncoImmunology

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Stimulator of interferon genes (STING) pathway activation predicts the effectiveness of targeting the PD-1/PD-L1 axis in lung cancer. Active IFN-γ signaling is a common feature in tumors that respond to PD-1/PD-L1 blockade. The connection between IFN-γ and STING signaling in cancer cells has not been documented. We showed that IFN-γ caused DNA damage and the accumulation of cytosolic dsDNA, leading to the activation of the cGAS- and IFI16-dependent STING pathway in lung adenocarcinoma cells. IFN-γ-induced iNOS expression and nitric oxide production were responsible for DNA damage and STING activation. Additional etoposide treatment enhanced IFN-γ-induced IFN-β and CCL5 expression. Tumor-infiltrating T cells stimulated with a combination of anti-CD3 and anti-PD-1 antibodies caused STING activation and increased IFN-β and CCL5 expression in lung adenocarcinoma. These effects were abrogated by the addition of an IFN-γ neutralizing antibody. Our results suggest that the activation of tumor-infiltrating T cells could alter the tumor microenvironment via the IFN-γ-mediated activation of STING signaling in cancer cells.

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“…Simultaneous administration of immune-enhancing agents can indeed improve antitumor immunity but is accompanied by a higher risk of immune-related adverse effects ( 21 ). Triple combination therapy, such as anti-PD-L1 antibody, poly-(ADP-ribose) polymerase inhibitor, and MEK inhibitor, was also applied to overcome resistance to anti-PD-L1 therapies in KRAS mutant cancer ( 22 ). Agonists targeting STING in combination with CTLA-4 or PD-1 inhibitor also exerted refreshing efficacy in the CRC model with complete tumor regression and long-lasting immune memory ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PCSK9 enhances the antitumor effect of PD-1 inhibitor in colorectal cancer by promoting the infiltration of CD8+ T cells and the exclusion of Treg cells

Wang

Liu

et al. 2022

Front. Immunol.

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Immunotherapy especially immune checkpoint inhibitors (ICIs) has brought favorable clinical results for numerous cancer patients. However, the efficacy of ICIs in colorectal cancer (CRC) is still unsatisfactory due to the poor median progression-free survival and overall survival. Here, based on the CRC models, we tried to elucidate novel relapse mechanisms during anti-PD-1 therapy. We found that PD-1 blockade elicited a mild antitumor effect in these tumor models with both increased CD8+ T cells and Treg cells. Gene mapping analysis indicated that proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, transforming growth factor-β (TGF-β), and CD36 were unexpectedly upregulated during PD-1 blockade. To investigate the critical role of these proteins especially PCSK9 in tumor growth, anti-PCSK9 antibody in combination with anti-PD-1 antibody was employed to block PCSK9 and PD-1 simultaneously in CRC. Data showed that neutralizing PCSK9 during anti-PD-1 therapy elicited a synergetic antitumor effect with increased CD8+ T-cell infiltration and inflammatory cytokine releases. Moreover, the proportion of Treg cells was significantly reduced by co-inhibiting PCSK9 and PD-1. Overall, inhibiting PCSK9 can further enhance the antitumor effect of anti-PD-1 therapy in CRC, indicating that targeting PCSK9 could be a promising approach to potentiate ICI efficacy.

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MEK Inhibition Remodels the Immune Landscape of Mutant KRAS Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors

Cited by 34 publications

References 50 publications

STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

IFN-γ activates the tumor cell-intrinsic STING pathway through the induction of DNA damage and cytosolic dsDNA formation

Inhibition of PCSK9 enhances the antitumor effect of PD-1 inhibitor in colorectal cancer by promoting the infiltration of CD8+ T cells and the exclusion of Treg cells

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