Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma
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Abstract
Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC.
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Immune-related findings likely reflect the intricate interplay between malignant cells and the tumor microenvironment.
“Such findings are frequently reported in bulk tumor transcriptome studies and likely reflect the intricate interplay between malignant cells and the tumor microenvironment (TME) [59–61].”
From PPP1R18-mediated activation of Wnt/β-catenin and EMT is dependent on ERK signaling in clear cell renal cell carcinoma (2026) · cites this paper as [61]
The Results section ('Tertiary lymphoid structures are associated with ER'; page unavailable) reports immune-cell infiltration and adaptive-immune signatures in tumor transcriptomic data. The Methods ('RNA Sequencing Analysis'; page unavailable) also describes inferring immune-cell populations from tumor RNA-seq. These passages support the tumor-microenvironment aspect, but do not establish that the findings reflect interplay specifically between malignant cells and the microenvironment, or that such findings are frequently reported across bulk-transcriptome studies. (LLM, conf=0.79)
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- [35]Chowdhury PS, Chamoto K, Kumar A, Honjo T. PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8 + T cells and facilitates anti–PD-1 therapy. Cancer Immunol Res. 2018; 6(11): 1375– 1387. doi: 10.1158/2326-6066.CIR-18-0095/470594/AM/PPAR-INDUCED-FATTY-ACID-OXIDATION-IN-T-CELLS 30143538 · DOI
- [39]Leidner R, Sanjuan Silva N, Huang H, Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. New England Journal of Medicine. 2022; 386(22): 2112– 2119. doi: 10.1056/NEJMOA2119662/SUPPL_FILE/NEJMOA2119662_DATA-SHARING.PDF 35648703 PMC9531755 · DOI
- [41]Motzer RJ, Penkov K, Haanen J, Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New England Journal of Medicine. 2019; 380(12): 1103– 1115. doi: 10.1056/NEJMOA1816047/SUPPL_FILE/NEJMOA1816047_DATA-SHARING.PDF 30779531 PMC6716603 · DOI
Cited by
Sorted by citations
Ji, X., Yun, Y., Zhu, Z., Wu, T., Ruan, M., Fan, Y., & Zhang, Q. (2026) · Cancer Cell International · doi:10.1186/s12935-026-04266-7
“Such findings are frequently reported in bulk tumor transcriptome studies and likely reflect the intricate interplay between malignant cells and the tumor microenvironment (TME) [59–61].”
- Authors
- Jammihal, T., Saliby, R. M., Labaki, C., Soulati, H., Gallegos, J., Peris, A., McCurry, D., Yu, C., Shah, V., Poduval, D., El Zarif, T., El Ahmar, N., Laimon, Y. N., Eid, M., Sheshdeh, A. B., Krajewski, K. M., Büttner, F. A., Schwab, M., Heng, D., Casellas, R. C., Rai, K., Zacharias Millward, N. M., Msaouel, P., Karam, J., Signoretti, S., Van Allen, E., Choueiri, T. K., Braun, D. A., & Shukla, S. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Beth Israel Deaconess Medical Center (US)
- Yale University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- University of Calgary (CA)
- Corresponding author
- Choueiri, Toni K.
- Braun, David A.
- Shukla, Sachet A.
- ORCID
- Jammihal, Tejas
- Saliby, Renee Maria
- Labaki, Chris
- Gallegos, Juan
- McCurry, Dustin
- Shah, Valisha
- Poduval, Deepak
- El Zarif, Talal
- Laimon, Yasmin Nabil
- Eid, Marc
- Krajewski, Katherine M.
- Büttner, Florian A.
- Schwab, Matthias
- Casellas, Rafael C.
- Rai, Kunal
- Msaouel, Pavlos
- Karam, Jose
- Signoretti, Sabina
- Van Allen, Eliezer
- Choueiri, Toni K.
- Braun, David A.
- Shukla, Sachet A.
- Venue
- Nature Cancer
- Published
- 2025-01-09
- Volume
- 6
- Issue
- 2
- Pages
- 372-384
- ISSN
- 2662-1347 (ISSN-L)
- PMC
- PMC12121501
- OpenAlex
- W4406221897
- Cited by
- 38
- References
- 72
- Citations by year
- 2026: 22 · 2025: 16
- FWCI
- 15.74
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Cancer (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services (5P30CA006516-56)
- Bristol-Myers Squibb
- Pfizer (10.13039/100009945)
- Cancer Prevention and Research Institute of Texas (RR220009)
- Dana-Farber/Harvard Cancer Center (2P50CA101942-16)
- Deutsche Forschungsgemeinschaft (EXC2180)
- National Institutes of Health (1r37ca279822-01)
- University of Texas MD Anderson Cancer Center
- National Cancer Institute (R37 CA279822, P50CA101942, P30CA006516, P30CA016359)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- immune checkpoint inhibitors, clear cell renal cell carcinoma, metastatic renal cell carcinoma, tertiary lymphoid structures, B cell receptor signaling, cytotoxic T lymphocytes, tumor microenvironment, VEGFR inhibitors, PD-1/PD-L1 inhibitors, immunotherapy response prediction, cancer metabolism
- MeSH terms
- Immune Checkpoint Inhibitors, Aged, Carcinoma, Renal Cell, Female, Humans, Immunotherapy, Kidney Neoplasms, Male, Middle Aged, Tumor Microenvironment, B7-H1 Antigen, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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