Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer
Recent advances in immunotherapy have reshaped the clinical management of lung cancer, and immune checkpoint inhibitors (ICIs) are now first-line treatment for advanced lung cancer. However, the majority of patients do not respond to ICIs as single agents, and many develop resistance after initial r...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/14/3595 |
| _version_ | 1797527427523543040 |
|---|---|
| author | Pasquale Saggese Cesar A. Martinez Linh M. Tran Raymond Lim Camelia Dumitras Tristan Grogan David Elashoff Ramin Salehi-Rad Steven M. Dubinett Bin Liu Claudio Scafoglio |
| author_facet | Pasquale Saggese Cesar A. Martinez Linh M. Tran Raymond Lim Camelia Dumitras Tristan Grogan David Elashoff Ramin Salehi-Rad Steven M. Dubinett Bin Liu Claudio Scafoglio |
| author_sort | Pasquale Saggese |
| collection | DOAJ |
| description | Recent advances in immunotherapy have reshaped the clinical management of lung cancer, and immune checkpoint inhibitors (ICIs) are now first-line treatment for advanced lung cancer. However, the majority of patients do not respond to ICIs as single agents, and many develop resistance after initial responses. Therefore, there is urgent need to improve the current ICI strategies. Murine models currently available for pre-clinical studies have serious limitations for evaluating novel immunotherapies. GEMMs are reliable and predictable models driven by oncogenic mutations mirroring those found in cancer patients. However, they lack the mutational burden of human cancers and thus do not elicit proper immune surveillance. Carcinogen-induced models are characterized by mutational burden that more closely resembles human cancer, but they often require extremely long experimental times with inconsistent results. Here, we present a hybrid model in which genetically engineered mice are exposed to the carcinogen <i>N</i>-Methyl-<i>N</i>-Nitrosourea (MNU) to increase tumor mutational burden (TMB), induce early-stage immune responses, and enhance susceptibility to ICIs. We anticipate that this model will be useful for pre-clinical evaluation of novel immunotherapies. |
| first_indexed | 2024-03-10T09:43:41Z |
| format | Article |
| id | doaj.art-0c4db9c95236443496ef12672b3639af |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:43:41Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0c4db9c95236443496ef12672b3639af2023-11-22T03:25:58ZengMDPI AGCancers2072-66942021-07-011314359510.3390/cancers13143595Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung CancerPasquale Saggese0Cesar A. Martinez1Linh M. Tran2Raymond Lim3Camelia Dumitras4Tristan Grogan5David Elashoff6Ramin Salehi-Rad7Steven M. Dubinett8Bin Liu9Claudio Scafoglio10Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADepartment of Medicine Statistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADepartment of Medicine Statistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USADivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USARecent advances in immunotherapy have reshaped the clinical management of lung cancer, and immune checkpoint inhibitors (ICIs) are now first-line treatment for advanced lung cancer. However, the majority of patients do not respond to ICIs as single agents, and many develop resistance after initial responses. Therefore, there is urgent need to improve the current ICI strategies. Murine models currently available for pre-clinical studies have serious limitations for evaluating novel immunotherapies. GEMMs are reliable and predictable models driven by oncogenic mutations mirroring those found in cancer patients. However, they lack the mutational burden of human cancers and thus do not elicit proper immune surveillance. Carcinogen-induced models are characterized by mutational burden that more closely resembles human cancer, but they often require extremely long experimental times with inconsistent results. Here, we present a hybrid model in which genetically engineered mice are exposed to the carcinogen <i>N</i>-Methyl-<i>N</i>-Nitrosourea (MNU) to increase tumor mutational burden (TMB), induce early-stage immune responses, and enhance susceptibility to ICIs. We anticipate that this model will be useful for pre-clinical evaluation of novel immunotherapies.https://www.mdpi.com/2072-6694/13/14/3595cancer immunotherapymurine modelslung cancer |
| spellingShingle | Pasquale Saggese Cesar A. Martinez Linh M. Tran Raymond Lim Camelia Dumitras Tristan Grogan David Elashoff Ramin Salehi-Rad Steven M. Dubinett Bin Liu Claudio Scafoglio Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer Cancers cancer immunotherapy murine models lung cancer |
| title | Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer |
| title_full | Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer |
| title_fullStr | Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer |
| title_full_unstemmed | Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer |
| title_short | Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer |
| title_sort | genotoxic treatment enhances immune response in a genetic model of lung cancer |
| topic | cancer immunotherapy murine models lung cancer |
| url | https://www.mdpi.com/2072-6694/13/14/3595 |
| work_keys_str_mv | AT pasqualesaggese genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT cesaramartinez genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT linhmtran genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT raymondlim genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT cameliadumitras genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT tristangrogan genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT davidelashoff genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT raminsalehirad genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT stevenmdubinett genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT binliu genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer AT claudioscafoglio genotoxictreatmentenhancesimmuneresponseinageneticmodeloflungcancer |