Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma
Background Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB).Methods This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherap...
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| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000974.full |
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| author | Alexander Huang Jeffrey C Thompson Christiana Davis Charuhas Deshpande Wei-Ting Hwang Seth Jeffries Tara C Mitchell Corey J Langer Steven M Albelda |
| author_facet | Alexander Huang Jeffrey C Thompson Christiana Davis Charuhas Deshpande Wei-Ting Hwang Seth Jeffries Tara C Mitchell Corey J Langer Steven M Albelda |
| author_sort | Alexander Huang |
| collection | DOAJ |
| description | Background Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB).Methods This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherapy-refractory advanced non-small cell lung cancer (NSCLC) patients and two independent melanoma cohorts treated with ICB. An antigen processing machinery (APM) score was generated utilizing eight genes associated with APM (B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, and HSP90AB1). Associations were made for therapeutic response, progression-free survival (PFS) and overall survival (OS).Results In NSCLC, the APM score was significantly higher in responders compared with non-responders (p=0.0001). An APM score above the median value for the cohort was associated with improved PFS (HR 0.34 (0.18 to 0.64), p=0.001) and OS (HR 0.44 (0.23 to 0.83), p=0.006). The APM score was correlated with an inflammation score based on the established T-cell-inflamed resistance gene expression profile (Pearson’s r=0.58, p<0.0001). However, the APM score better predicted response to ICB relative to the inflammation score with area under a receiving operating characteristics curve of 0.84 and 0.70 for PFS and OS, respectively. In a cohort of 14 high-risk resectable stage III/IV melanoma patients treated with neoadjuvant anti-PD1 ICB, a higher APM score was associated with improved disease-free survival (HR: 0.08 (0.01 to 0.50), p=0.0065). In an additional independent melanoma cohort of 27 metastatic patients treated with ICB, a higher APM score was associated with improved OS (HR 0.29 (0.09 to 0.89), p=0.044).Conclusion Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma. |
| format | Article |
| id | doaj-art-ee688b09a74b4b888bc01809fd2a86d6 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ee688b09a74b4b888bc01809fd2a86d62024-11-11T00:25:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000974Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanomaAlexander Huang0Jeffrey C Thompson1Christiana Davis2Charuhas Deshpande3Wei-Ting Hwang4Seth Jeffries5Tara C Mitchell6Corey J Langer7Steven M Albelda8Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Ontario, Canada1 Pulmonary and Critical Care, Thoracic Oncology Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA2 Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA3 Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA4 Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA2 Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA13 Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA2 Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA1University of Pennsylvania, Philadelphia, PA, USABackground Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB).Methods This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherapy-refractory advanced non-small cell lung cancer (NSCLC) patients and two independent melanoma cohorts treated with ICB. An antigen processing machinery (APM) score was generated utilizing eight genes associated with APM (B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, and HSP90AB1). Associations were made for therapeutic response, progression-free survival (PFS) and overall survival (OS).Results In NSCLC, the APM score was significantly higher in responders compared with non-responders (p=0.0001). An APM score above the median value for the cohort was associated with improved PFS (HR 0.34 (0.18 to 0.64), p=0.001) and OS (HR 0.44 (0.23 to 0.83), p=0.006). The APM score was correlated with an inflammation score based on the established T-cell-inflamed resistance gene expression profile (Pearson’s r=0.58, p<0.0001). However, the APM score better predicted response to ICB relative to the inflammation score with area under a receiving operating characteristics curve of 0.84 and 0.70 for PFS and OS, respectively. In a cohort of 14 high-risk resectable stage III/IV melanoma patients treated with neoadjuvant anti-PD1 ICB, a higher APM score was associated with improved disease-free survival (HR: 0.08 (0.01 to 0.50), p=0.0065). In an additional independent melanoma cohort of 27 metastatic patients treated with ICB, a higher APM score was associated with improved OS (HR 0.29 (0.09 to 0.89), p=0.044).Conclusion Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma.https://jitc.bmj.com/content/8/2/e000974.full |
| spellingShingle | Alexander Huang Jeffrey C Thompson Christiana Davis Charuhas Deshpande Wei-Ting Hwang Seth Jeffries Tara C Mitchell Corey J Langer Steven M Albelda Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma Journal for ImmunoTherapy of Cancer |
| title | Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma |
| title_full | Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma |
| title_fullStr | Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma |
| title_full_unstemmed | Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma |
| title_short | Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma |
| title_sort | gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non small cell lung cancer nsclc and melanoma |
| url | https://jitc.bmj.com/content/8/2/e000974.full |
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