Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma
The introduction of immune checkpoint blockade (ICB) has markedly improved outcomes for advanced melanoma. However, many patients develop resistance through unknown mechanisms. While combination ICB has improved response rate and progression-free survival, it substantially increases toxicity. Biomarkers to distinguish patients who would benefit from combination therapy versus aPD-1 remain elusive. We analyzed whole-exome sequencing of pretreatment tumors from four cohorts (<i>n</i> = 140) of ICB-naïve patients treated with aPD-1. High genomic heterogeneity and low ploidy robustly identified patients intrinsically resistant to aPD-1. To establish clinically actionable predictions, we optimized and validated a predictive model using ploidy and heterogeneity to confidently identify (90% PPV) patients with intrinsic resistance to and worse survival on aPD-1. We further observed that three of seven (43%) patients predicted to be intrinsically resistant to single-agent PD-1 ICB responded to combination ICB, suggesting that these patients may benefit disproportionately from combination ICB. These findings highlight the importance of heterogeneity and ploidy, nominating an approach toward clinical actionability.
Authors
- J. Jameson (ORCID: https://orcid.org/0009-0000-6980-2982)
- William Ge (ORCID: https://orcid.org/0000-0002-2278-8201)
- Haitham Elmarakeby (ORCID: https://orcid.org/0000-0002-4315-4347)
- Bastian Schilling (ORCID: https://orcid.org/0000-0001-8859-4103)
- Marta Holovatska (ORCID: https://orcid.org/0000-0002-0291-4960)
- Genevieve Marie Boland (ORCID: https://orcid.org/0000-0002-7522-6173)
- Karena Zhao (ORCID: https://orcid.org/0000-0003-3867-7474)
- Yingxiao Shi (ORCID: https://orcid.org/0000-0003-2783-9642)
- Keith T. Flaherty (ORCID: https://orcid.org/0000-0002-3402-0478)
- Amy Y. Huang (ORCID: https://orcid.org/0000-0002-6646-6503)
- Alexander Rösch (ORCID: https://orcid.org/0000-0002-0841-2574)
- Dirk Schadendorf (ORCID: https://orcid.org/0000-0003-3524-7858)
- Tyler J. Aprati (ORCID: https://orcid.org/0000-0003-1323-9697)
- Eliezer M. Van Allen (ORCID: https://orcid.org/0000-0002-0201-4444)
- Catherine H. Feng (ORCID: https://orcid.org/0000-0002-7413-9748)
- Dennie T. Frederick (ORCID: https://orcid.org/0000-0003-3355-5267)
- Catherine J. Wu (ORCID: https://orcid.org/0000-0002-3348-5054)
- Elisabeth Livingstone (ORCID: https://orcid.org/0000-0001-8279-9239)
- Cora A. Ricker (ORCID: https://orcid.org/0000-0003-1202-5603)
- Marc Glettig (ORCID: https://orcid.org/0000-0002-2512-7740)
- Samuel S. Freeman (ORCID: https://orcid.org/0000-0001-8285-0057)
- Lisa Zimmer (ORCID: https://orcid.org/0000-0002-3680-3521)
- Anne Zaremba (ORCID: https://orcid.org/0000-0002-6932-0489)
- Elizabeth I. Buchbinder (ORCID: https://orcid.org/0000-0002-7979-8953)
- Annette Wang
- Shariq Madha (ORCID: https://orcid.org/0000-0001-6022-6560)
- Soroush Saghafian (ORCID: https://orcid.org/0000-0002-9781-6561)
- Michael P. Manos (ORCID: https://orcid.org/0000-0003-0841-207X)
- Anita Giobbie‐Hurder (ORCID: https://orcid.org/0000-0003-2496-7737)
- Giuseppe Tarantino (ORCID: https://orcid.org/0000-0002-6078-6856)
- Brendan Reardon (ORCID: https://orcid.org/0000-0002-1716-5720)
- Luc G.T. Morris (ORCID: https://orcid.org/0000-0002-4417-2280)
- F. Stephen Hodi (ORCID: https://orcid.org/0000-0001-6825-091X)
- Natalie I. Vokes (ORCID: https://orcid.org/0000-0002-3766-5335)
- Rizwan Haq (ORCID: https://orcid.org/0000-0002-1290-9276)
- Jihye Park (ORCID: https://orcid.org/0000-0002-4451-2046)
- Jiajia Chen (ORCID: https://orcid.org/0000-0002-5378-6284)
- David Liu (ORCID: https://orcid.org/0000-0003-0346-5033)
- Andrew S. Lee (ORCID: https://orcid.org/0000-0002-2885-6316)
Institutions
- Worcester Polytechnic Institute (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Al-Azhar University (EG)
- Harvard University Press (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Essen University Hospital (DE)
- Universitätsklinikum Würzburg (DE)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1126/sciadv.adp4670
- Citations
- 4
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.13