In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies
Background Colorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with high-microsatellite instability, high tumor mutation burden, and intratumoral l...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-03-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004032.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849763696881958912 |
|---|---|
| author | Nicola Normanno Fabiana Tatangelo Piera Maiolino Stefania Scala Caterina Ieranò Dario Righelli Crescenzo D'Alterio Maria Napolitano Luigi Portella Giuseppina Rea Federica Auletta Sara Santagata Anna Maria Trotta Giuseppe Guardascione Federica Liotti Nella Prevete Antonio Luciano Antonio Barbieri Annabella Di Mauro Cristin Roma Riziero Esposito Abate Roberto Pacelli Rosa Marina Melillo |
| author_facet | Nicola Normanno Fabiana Tatangelo Piera Maiolino Stefania Scala Caterina Ieranò Dario Righelli Crescenzo D'Alterio Maria Napolitano Luigi Portella Giuseppina Rea Federica Auletta Sara Santagata Anna Maria Trotta Giuseppe Guardascione Federica Liotti Nella Prevete Antonio Luciano Antonio Barbieri Annabella Di Mauro Cristin Roma Riziero Esposito Abate Roberto Pacelli Rosa Marina Melillo |
| author_sort | Nicola Normanno |
| collection | DOAJ |
| description | Background Colorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with high-microsatellite instability, high tumor mutation burden, and intratumoral lymphocytic infiltration. Programmed death-ligand 1 (PD-L1)/PD-1 signaling was described in solid tumor cells. In melanoma, liver, and thyroid cancer cells, intrinsic PD-1 signaling activates oncogenic functions, while in lung cancer cells, it has a tumor suppressor effect. Our work aimed to evaluate the effects of the anti-PD-1 nivolumab (NIVO) on CRC cells.Methods In vitro NIVO-treated human colon cancer cells (HT29, HCT116, and LoVo) were evaluated for cell growth, chemo/radiotherapeutic sensitivity, apoptosis, and spheroid growth. Total RNA-seq was assessed in 6–24 hours NIVO-treated human colon cancer cells HT29 and HCT116 as compared with NIVO-treated PES43 human melanoma cells. In vivo mice carrying HT29 xenograft were intraperitoneally treated with NIVO, OXA (oxaliplatin), and NIVO+OXA, and the tumors were characterized for growth, apoptosis, and pERK1/2/pP38. Forty-eight human primary colon cancers were evaluated for PD-1 expression through immunohistochemistry.Results In PD-1+ human colon cancer cells, intrinsic PD-1 signaling significantly decreased proliferation and promoted apoptosis. On the contrary, NIVO promoted proliferation, reduced apoptosis, and protected PD-1+ cells from chemo/radiotherapy. Transcriptional profile of NIVO-treated HT29 and HCT116 human colon cancer cells revealed downregulation of BATF2, DRAM1, FXYD3, IFIT3, MT-TN, and TNFRSF11A, and upregulation of CLK1, DCAF13, DNAJC2, MTHFD1L, PRPF3, PSMD7, and SCFD1; the opposite regulation was described in NIVO-treated human melanoma PES43 cells. Differentially expressed genes (DEGs) were significantly enriched for interferon pathway, innate immune, cytokine-mediated signaling pathways. In vivo, NIVO promoted HT29 tumor growth, thus reducing OXA efficacy as revealed through significant Ki-67 increase, pERK1/2 and pP38 increase, and apoptotic cell reduction. Eleven out of 48 primary human colon cancer biopsies expressed PD-1 (22.9%). PD-1 expression is significantly associated with lower pT stage.Conclusions In PD-1+ human colon cancer cells, NIVO activates tumor survival pathways and could protect tumor cells from conventional therapies. |
| format | Article |
| id | doaj-art-b1c66c6327b04eacbccc9f2e0878a6d9 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b1c66c6327b04eacbccc9f2e0878a6d92025-08-20T03:05:21ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004032In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapiesNicola Normanno0Fabiana Tatangelo1Piera Maiolino2Stefania Scala3Caterina Ieranò4Dario Righelli5Crescenzo D'Alterio6Maria Napolitano7Luigi Portella8Giuseppina Rea9Federica Auletta10Sara Santagata11Anna Maria Trotta12Giuseppe Guardascione13Federica Liotti14Nella Prevete15Antonio Luciano16Antonio Barbieri17Annabella Di Mauro18Cristin Roma19Riziero Esposito Abate20Roberto Pacelli21Rosa Marina Melillo225 Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori, National Cancer Institute IRCCS Pascale Foundation, Napoli, ItalyPathology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyPharmacy, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyStatistical Sciences, University of Padua, Padua, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyMicroenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyInstitute of Endocrinology and Experimental Oncology (IEOS), CNR-NA1, Napoli, ItalyInstitute of Endocrinology and Experimental Oncology (IEOS), CNR-NA1, Napoli, ItalyAnimal Facility, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyAnimal Facility, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyPathology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyCell Biology and Biotherapy, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItalyCell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, ItalyAdvanced Biomedical Sciences, University of Naples Federico II, Napoli, ItalyInstitute of Endocrinology and Experimental Oncology (IEOS), CNR-NA1, Napoli, ItalyBackground Colorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with high-microsatellite instability, high tumor mutation burden, and intratumoral lymphocytic infiltration. Programmed death-ligand 1 (PD-L1)/PD-1 signaling was described in solid tumor cells. In melanoma, liver, and thyroid cancer cells, intrinsic PD-1 signaling activates oncogenic functions, while in lung cancer cells, it has a tumor suppressor effect. Our work aimed to evaluate the effects of the anti-PD-1 nivolumab (NIVO) on CRC cells.Methods In vitro NIVO-treated human colon cancer cells (HT29, HCT116, and LoVo) were evaluated for cell growth, chemo/radiotherapeutic sensitivity, apoptosis, and spheroid growth. Total RNA-seq was assessed in 6–24 hours NIVO-treated human colon cancer cells HT29 and HCT116 as compared with NIVO-treated PES43 human melanoma cells. In vivo mice carrying HT29 xenograft were intraperitoneally treated with NIVO, OXA (oxaliplatin), and NIVO+OXA, and the tumors were characterized for growth, apoptosis, and pERK1/2/pP38. Forty-eight human primary colon cancers were evaluated for PD-1 expression through immunohistochemistry.Results In PD-1+ human colon cancer cells, intrinsic PD-1 signaling significantly decreased proliferation and promoted apoptosis. On the contrary, NIVO promoted proliferation, reduced apoptosis, and protected PD-1+ cells from chemo/radiotherapy. Transcriptional profile of NIVO-treated HT29 and HCT116 human colon cancer cells revealed downregulation of BATF2, DRAM1, FXYD3, IFIT3, MT-TN, and TNFRSF11A, and upregulation of CLK1, DCAF13, DNAJC2, MTHFD1L, PRPF3, PSMD7, and SCFD1; the opposite regulation was described in NIVO-treated human melanoma PES43 cells. Differentially expressed genes (DEGs) were significantly enriched for interferon pathway, innate immune, cytokine-mediated signaling pathways. In vivo, NIVO promoted HT29 tumor growth, thus reducing OXA efficacy as revealed through significant Ki-67 increase, pERK1/2 and pP38 increase, and apoptotic cell reduction. Eleven out of 48 primary human colon cancer biopsies expressed PD-1 (22.9%). PD-1 expression is significantly associated with lower pT stage.Conclusions In PD-1+ human colon cancer cells, NIVO activates tumor survival pathways and could protect tumor cells from conventional therapies.https://jitc.bmj.com/content/10/3/e004032.full |
| spellingShingle | Nicola Normanno Fabiana Tatangelo Piera Maiolino Stefania Scala Caterina Ieranò Dario Righelli Crescenzo D'Alterio Maria Napolitano Luigi Portella Giuseppina Rea Federica Auletta Sara Santagata Anna Maria Trotta Giuseppe Guardascione Federica Liotti Nella Prevete Antonio Luciano Antonio Barbieri Annabella Di Mauro Cristin Roma Riziero Esposito Abate Roberto Pacelli Rosa Marina Melillo In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies Journal for ImmunoTherapy of Cancer |
| title | In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies |
| title_full | In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies |
| title_fullStr | In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies |
| title_full_unstemmed | In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies |
| title_short | In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies |
| title_sort | in pd 1 human colon cancer cells nivolumab promotes survival and could protect tumor cells from conventional therapies |
| url | https://jitc.bmj.com/content/10/3/e004032.full |
| work_keys_str_mv | AT nicolanormanno inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT fabianatatangelo inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT pieramaiolino inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT stefaniascala inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT caterinaierano inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT dariorighelli inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT crescenzodalterio inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT marianapolitano inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT luigiportella inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT giuseppinarea inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT federicaauletta inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT sarasantagata inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT annamariatrotta inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT giuseppeguardascione inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT federicaliotti inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT nellaprevete inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT antonioluciano inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT antoniobarbieri inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT annabelladimauro inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT cristinroma inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT rizieroespositoabate inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT robertopacelli inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies AT rosamarinamelillo inpd1humancoloncancercellsnivolumabpromotessurvivalandcouldprotecttumorcellsfromconventionaltherapies |