Multicellular immune ecotypes within solid tumors predict real-world therapeutic benefits with immune checkpoint inhibitors
Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet predicting patient response remains a major challenge. Carcinoma ecotypes, which capture the cancer-immune interactions, show promise as prognostic biomarkers but remain untested in real-world settings. We compile and analyze the ORIEN Avatar ICI cohort of 1610 patients with matched gene expression data from a broader dataset of 14,997 individuals. Using EcoTyper-based immunophenotyping, we define ecotypes and assess their prognostic value across cancers, with a focused analysis in melanoma. Distinct cell states and ecotypes are consistently associated with survival outcomes across cancer types. We further develop a melanoma-specific ICI predictive model and validate it using data from the phase III ECOG-ACRIN E1609 trial as well as in external harmonized melanoma datasets. Together, these findings establish an ecotype-based framework and provide real-world evidence for their translational utility as clinically actionable biomarkers with prognostic and predictive value to guide ICI therapy.
Authors
- George J. Weiner (ORCID: https://orcid.org/0000-0003-3427-0562)
- Aakrosh Ratan (ORCID: https://orcid.org/0000-0002-0782-3056)
- Ahmad A. Tarhini (ORCID: https://orcid.org/0000-0002-3193-9702)
- Julian A. Marin‐Acevedo (ORCID: https://orcid.org/0000-0001-7067-173X)
- Susanne M. Arnold (ORCID: https://orcid.org/0000-0001-6542-9551)
- Paulo C. Rodrı́guez (ORCID: https://orcid.org/0000-0001-7480-6566)
- Patrick Hwu (ORCID: https://orcid.org/0000-0002-8293-1313)
- Alex C. Soupir (ORCID: https://orcid.org/0000-0003-1251-9179)
- Martin D. McCarter (ORCID: https://orcid.org/0000-0001-8174-1713)
- Michael D. Radmacher
- Howard Colman (ORCID: https://orcid.org/0000-0002-4027-7317)
- Igor Puzanov (ORCID: https://orcid.org/0000-0002-9803-3497)
- Tingyi Li
- William S. Dalton (ORCID: https://orcid.org/0000-0003-2582-0454)
- Michelle L. Churchman (ORCID: https://orcid.org/0000-0002-6560-1056)
- Shridar Ganesan (ORCID: https://orcid.org/0000-0002-5404-3044)
- Phaedra Agius (ORCID: https://orcid.org/0000-0002-1688-992X)
- Vineeth Sukrithan (ORCID: https://orcid.org/0000-0002-5878-9900)
- Bodour Salhia (ORCID: https://orcid.org/0000-0003-3843-3621)
- Islam Eljilany (ORCID: https://orcid.org/0000-0001-6387-5419)
- Abdul Rafeh Naqash (ORCID: https://orcid.org/0000-0001-7622-720X)
- Xuefeng Wang (ORCID: https://orcid.org/0000-0001-5775-408X)
Institutions
- Rutgers, The State University of New Jersey (US)
- University of Southern California (US)
- Indiana University Health (US)
- Roswell Park Comprehensive Cancer Center (US)
- University of Utah (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Markey Cancer Center (US)
- Moffitt Cancer Center (US)
- Indiana Cancer Consortium (US)
- University of Colorado Cancer Center (US)
- University of Iowa Health Care (US)
- Rutgers Cancer Institute (US)
- University of Oklahoma Health Sciences Center (US)
- University of Virginia (US)
- Indiana University – Purdue University Indianapolis (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-13
- DOI
- https://doi.org/10.1038/s41467-025-65016-3
- Citations
- 3
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- American College of Radiology Imaging Network
- Moffitt Cancer Center
- ECOG-ACRIN Cancer Research Group
- Bundesinstitut für Bau- Stadt- und Raumforschung
- National Institutes of Health
- National Cancer Institute