Clinical benefit from immunotherapy in patients with SCLC is associated with tumor capacity for antigen presentation Journal Article
| Authors: | Rudin, C. M.; Balli, D.; Lai, W. V.; Richards, A. L.; Nguyen, E.; Egger, J. V.; Choudhury, N. J.; Sen, T.; Chow, A.; Poirier, J. T.; Geese, W. J.; Hellmann, M. D.; Forslund, A. |
| Article Title: | Clinical benefit from immunotherapy in patients with SCLC is associated with tumor capacity for antigen presentation |
| Abstract: | Introduction: A small percentage of patients with SCLC experience durable responses to immune checkpoint blockade (ICB). Defining determinants of immune response may nominate strategies to broaden the efficacy of immunotherapy in patients with SCLC. Prior studies have been limited by small numbers or concomitant chemotherapy administration. Methods: CheckMate 032, a multicenter, open-label, phase 1/2 trial evaluating nivolumab alone or with ipilimumab was the largest study of ICB alone in patients with SCLC. We performed comprehensive RNA sequencing of 286 pretreatment SCLC tumor samples, assessing outcome on the basis of defined SCLC subtypes (SCLC-A, -N, -P, and -Y), and expression signatures associated with durable benefit, defined as progression-free survival more than or equal to 6 months. Potential biomarkers were further explored by immunohistochemistry. Results: None of the subtypes were associated with survival. Antigen presentation machinery signature (p = 0.000032) and presence of more than or equal to 1% infiltrating CD8+ T cells by immunohistochemistry (hazard ratio = 0.51, 95% confidence interval: 0.27–0.95) both correlated with survival in patients treated with nivolumab. Pathway enrichment analysis revealed the association between durable benefit from immunotherapy and antigen processing and presentation. Analysis of epigenetic determinants of antigen presentation identified LSD1 gene expression as a correlate of worse survival outcomes for patients treated with either nivolumab or the combination of nivolumab and ipilimumab. Conclusions: Tumor antigen processing and presentation is a key correlate of ICB efficacy in patients with SCLC. As antigen presentation machinery is frequently epigenetically suppressed in SCLC, this study defines a targetable mechanism by which we might improve clinical benefit of ICB for patients with SCLC. © 2023 International Association for the Study of Lung Cancer |
| Keywords: | clinical trial; ipilimumab; phase 2 clinical trial; lung neoplasms; pathology; lung tumor; antigen presentation; immunotherapy; epigenetics; multicenter study; phase 1 clinical trial; small cell lung cancer; small cell lung carcinoma; immune checkpoint blockade; nivolumab; humans; human |
| Journal Title: | Journal of Thoracic Oncology |
| Volume: | 18 |
| Issue: | 9 |
| ISSN: | 1556-0864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2023-09-01 |
| Start Page: | 1222 |
| End Page: | 1232 |
| Language: | English |
| DOI: | 10.1016/j.jtho.2023.05.008 |
| PUBMED: | 37210008 |
| PROVIDER: | scopus |
| PMCID: | PMC10524620 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA0098748) acknowledged in PubMed and PDF -- MSK corresponding author is Charles Rudin -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work