Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer
The majority of colorectal cancers (CRCs) are microsatellite stable (MSS) and resistant to immunotherapy. The current study explores the possibility of using oncolytic reovirus to sensitize MSS CRC to immune checkpoint inhibition. While reovirus reduced metabolic activity among KRASMut cells, microa...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1018767/full |
| _version_ | 1811234540241289216 |
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| author | Titto Augustine Peter John Tyler Friedman Tyler Friedman Jeeshan Jiffry Hillary Guzik Rifat Mannan Riya Gupta Riya Gupta Catherine Delano John M. Mariadason Xingxing Zang Xingxing Zang Xingxing Zang Radhashree Maitra Radhashree Maitra Radhashree Maitra Sanjay Goel Sanjay Goel |
| author_facet | Titto Augustine Peter John Tyler Friedman Tyler Friedman Jeeshan Jiffry Hillary Guzik Rifat Mannan Riya Gupta Riya Gupta Catherine Delano John M. Mariadason Xingxing Zang Xingxing Zang Xingxing Zang Radhashree Maitra Radhashree Maitra Radhashree Maitra Sanjay Goel Sanjay Goel |
| author_sort | Titto Augustine |
| collection | DOAJ |
| description | The majority of colorectal cancers (CRCs) are microsatellite stable (MSS) and resistant to immunotherapy. The current study explores the possibility of using oncolytic reovirus to sensitize MSS CRC to immune checkpoint inhibition. While reovirus reduced metabolic activity among KRASMut cells, microarray/computational analysis revealed microsatellite status-oriented activation of immune-response pathways. Reovirus plus anti-PD-1 treatment increased cell death among MSS cells ex vivo. Reduced tumorigenicity and proliferative index, and increased apoptosis were evident among CT26 [MSS, KRASMut], but not in MC38 [microsatellite unstable/MSI, KRASWt] syngeneic mouse models under combinatorial treatment. PD-L1-PD-1 signaling axis were differentially altered among CT26/MC38 models. Combinatorial treatment activated the innate immune system, pattern recognition receptors, and antigen presentation markers. Furthermore, we observed the reduction of immunosuppressive macrophages and expansion of effector T cell subsets, as well as reduction in T cell exhaustion. The current investigation sheds light on the immunological mechanisms of the reovirus-anti-PD-1 combination to reduce the growth of MSS CRC. |
| first_indexed | 2024-04-12T11:38:05Z |
| format | Article |
| id | doaj.art-ea7c3c86a49c409689ec5946a20dbf40 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T11:38:05Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-ea7c3c86a49c409689ec5946a20dbf402022-12-22T03:34:47ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-10-011210.3389/fonc.2022.10187671018767Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancerTitto Augustine0Peter John1Tyler Friedman2Tyler Friedman3Jeeshan Jiffry4Hillary Guzik5Rifat Mannan6Riya Gupta7Riya Gupta8Catherine Delano9John M. Mariadason10Xingxing Zang11Xingxing Zang12Xingxing Zang13Radhashree Maitra14Radhashree Maitra15Radhashree Maitra16Sanjay Goel17Sanjay Goel18Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Neuroscience, Florida State University, Tallahassee, FL, United StatesDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesAnalytical Imaging Facility, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Pathology, City of Hope, Duarte, CA, United StatesDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Computer Science, Columbia University, New York, NY, United StatesDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesGastrointestinal Cancers Program and Oncogenic Transcription Laboratory, Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Melbourne, VIC, AustraliaDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Urology, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States0Department of Biology, Yeshiva University, New York, NY, United StatesDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Medical Oncology, Montefiore Medical Center, Bronx, NY, United StatesThe majority of colorectal cancers (CRCs) are microsatellite stable (MSS) and resistant to immunotherapy. The current study explores the possibility of using oncolytic reovirus to sensitize MSS CRC to immune checkpoint inhibition. While reovirus reduced metabolic activity among KRASMut cells, microarray/computational analysis revealed microsatellite status-oriented activation of immune-response pathways. Reovirus plus anti-PD-1 treatment increased cell death among MSS cells ex vivo. Reduced tumorigenicity and proliferative index, and increased apoptosis were evident among CT26 [MSS, KRASMut], but not in MC38 [microsatellite unstable/MSI, KRASWt] syngeneic mouse models under combinatorial treatment. PD-L1-PD-1 signaling axis were differentially altered among CT26/MC38 models. Combinatorial treatment activated the innate immune system, pattern recognition receptors, and antigen presentation markers. Furthermore, we observed the reduction of immunosuppressive macrophages and expansion of effector T cell subsets, as well as reduction in T cell exhaustion. The current investigation sheds light on the immunological mechanisms of the reovirus-anti-PD-1 combination to reduce the growth of MSS CRC.https://www.frontiersin.org/articles/10.3389/fonc.2022.1018767/fullcolorectal cancertranslationalcombinatorial therapyreovirusanti-PD-1immune checkpoint |
| spellingShingle | Titto Augustine Peter John Tyler Friedman Tyler Friedman Jeeshan Jiffry Hillary Guzik Rifat Mannan Riya Gupta Riya Gupta Catherine Delano John M. Mariadason Xingxing Zang Xingxing Zang Xingxing Zang Radhashree Maitra Radhashree Maitra Radhashree Maitra Sanjay Goel Sanjay Goel Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer Frontiers in Oncology colorectal cancer translational combinatorial therapy reovirus anti-PD-1 immune checkpoint |
| title | Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer |
| title_full | Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer |
| title_fullStr | Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer |
| title_full_unstemmed | Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer |
| title_short | Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer |
| title_sort | potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer |
| topic | colorectal cancer translational combinatorial therapy reovirus anti-PD-1 immune checkpoint |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1018767/full |
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