PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness
PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against -mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2019-01, Vol.79 (2), p.311-319 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Shen, Jianfeng Zhao, Wei Ju, Zhenlin Wang, Lulu Peng, Yang Labrie, Marilyne Yap, Timothy A Mills, Gordon B Peng, Guang |
| description | PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against
-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring
mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of
mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS-STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. SIGNIFICANCE: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer. |
| doi_str_mv | 10.1158/0008-5472.CAN-18-1003 |
| format | Article |
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-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring
mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of
mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS-STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. SIGNIFICANCE: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-18-1003</identifier><identifier>PMID: 30482774</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antibodies - immunology ; Antibodies - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - immunology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; B7-H1 Antigen - antagonists & inhibitors ; B7-H1 Antigen - immunology ; Cell Line, Tumor ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - immunology ; DNA - genetics ; DNA - immunology ; Drug Synergism ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Membrane Proteins - immunology ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Nude ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - immunology ; Poly(ADP-ribose) Polymerase Inhibitors - immunology ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Signal Transduction - drug effects ; Signal Transduction - immunology</subject><ispartof>Cancer research (Chicago, Ill.), 2019-01, Vol.79 (2), p.311-319</ispartof><rights>2018 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c581t-3cb38ca6b5f607babaeabacc65a04dcfa1b557920fcce2e025382dec9df785e13</citedby><cites>FETCH-LOGICAL-c581t-3cb38ca6b5f607babaeabacc65a04dcfa1b557920fcce2e025382dec9df785e13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30482774$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shen, Jianfeng</creatorcontrib><creatorcontrib>Zhao, Wei</creatorcontrib><creatorcontrib>Ju, Zhenlin</creatorcontrib><creatorcontrib>Wang, Lulu</creatorcontrib><creatorcontrib>Peng, Yang</creatorcontrib><creatorcontrib>Labrie, Marilyne</creatorcontrib><creatorcontrib>Yap, Timothy A</creatorcontrib><creatorcontrib>Mills, Gordon B</creatorcontrib><creatorcontrib>Peng, Guang</creatorcontrib><title>PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against
-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring
mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of
mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS-STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. SIGNIFICANCE: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.</description><subject>Animals</subject><subject>Antibodies - immunology</subject><subject>Antibodies - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - immunology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>B7-H1 Antigen - antagonists & inhibitors</subject><subject>B7-H1 Antigen - immunology</subject><subject>Cell Line, Tumor</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - immunology</subject><subject>DNA - genetics</subject><subject>DNA - immunology</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>Genes, BRCA1</subject><subject>Genes, BRCA2</subject><subject>Humans</subject><subject>Membrane Proteins - immunology</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Nude</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - immunology</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - immunology</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVke1OwjAUhhujEfy4BE1vYNhuK6t_TGAikhA1iL-b7uyUTaBbVjDhJrxmuyBEfzRN0_M8bd6XkBvOepwLeccYk4GIk7CXDl4CLgPOWHRCulxEMkjiWJyS7nGmQy6c-_RHwZk4J52IxTJMkrhLvt8Gs7eSzptyscDG0U2B9H0-eRkHj1ijzdFu6GS93lqkM3R1ZR1SbXM6soW2gHtgXmCja9xuSqAjY0rQsKOVOYBpgbCsq9KrhqsKljpHOvHqg99PDmfpwKJzV-TM6JXD69_9knw8jebpczB9HU_SwTQAIfkmiCCLJOh-JkyfJZnONPoF0BeaxTkYzTMhkvuQGQAMkYU-lDBHuM9NIgXy6JI87L31NltjDv4bjV6puinXutmpSpfq_40tC7WovlRfSMlY6AViL4Cmcq5Bc2Q5U21Bqg1fteErX5DiUrUFee7278NH6tBI9APrrpA9</recordid><startdate>20190115</startdate><enddate>20190115</enddate><creator>Shen, Jianfeng</creator><creator>Zhao, Wei</creator><creator>Ju, Zhenlin</creator><creator>Wang, Lulu</creator><creator>Peng, Yang</creator><creator>Labrie, Marilyne</creator><creator>Yap, Timothy A</creator><creator>Mills, Gordon B</creator><creator>Peng, Guang</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20190115</creationdate><title>PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness</title><author>Shen, Jianfeng ; Zhao, Wei ; Ju, Zhenlin ; Wang, Lulu ; Peng, Yang ; Labrie, Marilyne ; Yap, Timothy A ; Mills, Gordon B ; Peng, Guang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c581t-3cb38ca6b5f607babaeabacc65a04dcfa1b557920fcce2e025382dec9df785e13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antibodies - immunology</topic><topic>Antibodies - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - immunology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>B7-H1 Antigen - antagonists & inhibitors</topic><topic>B7-H1 Antigen - immunology</topic><topic>Cell Line, Tumor</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - immunology</topic><topic>DNA - genetics</topic><topic>DNA - immunology</topic><topic>Drug Synergism</topic><topic>Female</topic><topic>Genes, BRCA1</topic><topic>Genes, BRCA2</topic><topic>Humans</topic><topic>Membrane Proteins - immunology</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Nude</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - immunology</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shen, Jianfeng</creatorcontrib><creatorcontrib>Zhao, Wei</creatorcontrib><creatorcontrib>Ju, Zhenlin</creatorcontrib><creatorcontrib>Wang, Lulu</creatorcontrib><creatorcontrib>Peng, Yang</creatorcontrib><creatorcontrib>Labrie, Marilyne</creatorcontrib><creatorcontrib>Yap, Timothy A</creatorcontrib><creatorcontrib>Mills, Gordon B</creatorcontrib><creatorcontrib>Peng, Guang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shen, Jianfeng</au><au>Zhao, Wei</au><au>Ju, Zhenlin</au><au>Wang, Lulu</au><au>Peng, Yang</au><au>Labrie, Marilyne</au><au>Yap, Timothy A</au><au>Mills, Gordon B</au><au>Peng, Guang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2019-01-15</date><risdate>2019</risdate><volume>79</volume><issue>2</issue><spage>311</spage><epage>319</epage><pages>311-319</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against
-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring
mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of
mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS-STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. SIGNIFICANCE: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.</abstract><cop>United States</cop><pmid>30482774</pmid><doi>10.1158/0008-5472.CAN-18-1003</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2019-01, Vol.79 (2), p.311-319 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Antibodies - immunology Antibodies - pharmacology Antineoplastic Combined Chemotherapy Protocols - immunology Antineoplastic Combined Chemotherapy Protocols - pharmacology B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - immunology Cell Line, Tumor Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - immunology DNA - genetics DNA - immunology Drug Synergism Female Genes, BRCA1 Genes, BRCA2 Humans Membrane Proteins - immunology Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Nude Ovarian Neoplasms - drug therapy Ovarian Neoplasms - immunology Poly(ADP-ribose) Polymerase Inhibitors - immunology Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Signal Transduction - drug effects Signal Transduction - immunology |
| title | PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness |
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