Baseline intratumoral TCRbeta; and TCRgamma; repertoires predict response to immune checkpoint inhibitors in advanced renal cell carcinoma
- 1Translational Oncology Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Alvaro Cunqueiro, Carretera Clara Campoamor, 341,
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced renal cell carcinoma (RCC), yet only a subset of patients derives durable clinical benefit and no robust predictive biomarkers have been implemented in routine clinical practice. As T-cell receptor (TCR)-mediated antigen recognition underlies effective antitumor immunity, characterization of the intratumoral TCR repertoire may provide clinically relevant information for patient stratification. Here, we evaluated the predictive value of the baseline intratumoral TCR{beta} and TCR{gamma} repertoires in a real-world cohort of patients with advanced RCC treated predominantly with first-line immune checkpoint inhibitor-based regimens. Responders exhibited a significantly more even TCR{beta} repertoire together with increased TCR{gamma} diversity and clonal richness, whereas non-responders showed greater TCR{gamma} clonal dominance. In addition, the preferential usage of specific TRBV genes, including TRBV5.7, TRBV7.1, and TRBV18, was associated with clinical response and longer progression-free survival. In this exploratory cohort, integration of the most informative TCR{beta} and TCR{gamma} variables into a combined random forest model yielded an area under the receiver operating characteristic curve of 0.90 in leave-one-out cross-validation, with 100% sensitivity and 81.8% specificity at the selected threshold. To our knowledge, this is the first study to simultaneously characterize baseline intratumoral TCR{beta} and TCR{gamma} repertoires in patients with advanced RCC predominantly receiving first-line immune checkpoint blockade. These findings support baseline intratumoral TCR repertoire features as candidate tissue biomarkers for pretreatment patient stratification and provide a rationale for the prospective validation of TCR repertoire profiling as a predictor of immunotherapy benefit in RCC.
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BibTeX
@misc{gonzalez2026baseline,
title = {{Baseline intratumoral TCRbeta; and TCRgamma; repertoires predict response to immune checkpoint inhibitors in advanced renal cell carcinoma}},
author = {M. Pino Gonzalez and M. E. Lazaro Quintela and G. d. V. Oria de Rueda and M. Duenas Porto and I. Alonso Alvarez and A. Francisco Fernandez and M. P. San Miguel Fraile and J. A. Ortiz Rey and M. Gallardo Gomez and L. Carracedo Videira and S. Gallach Garcia and E. Jantus Lewintre and M. Martinez Fernandez},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.26361892},
url = {https://www.medrxiv.org/content/10.64898/2026.09.01.26361892v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Baseline intratumoral TCRbeta; and TCRgamma; repertoires predict response to immune checkpoint inhibitors in advanced renal cell carcinoma
AU - M. Pino Gonzalez
AU - M. E. Lazaro Quintela
AU - G. d. V. Oria de Rueda
AU - M. Duenas Porto
AU - I. Alonso Alvarez
AU - A. Francisco Fernandez
AU - M. P. San Miguel Fraile
AU - J. A. Ortiz Rey
AU - M. Gallardo Gomez
AU - L. Carracedo Videira
AU - S. Gallach Garcia
AU - E. Jantus Lewintre
AU - M. Martinez Fernandez
PY - 2026
DA - 2026/09/01
PB - medRxiv
DO - 10.64898/2026.09.01.26361892
UR - https://www.medrxiv.org/content/10.64898/2026.09.01.26361892v1
AB - Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced renal cell carcinoma (RCC), yet only a subset of patients derives durable clinical benefit and no robust predictive biomarkers have been implemented in routine clinical practice. As T-cell receptor (TCR)-mediated antigen recognition underlies effective antitumor immunity, characterization of the intratumoral TCR repertoire may provide clinically relevant information for patient stratification. Here, we evaluated the predictive value of the baseline intratumoral TCR{beta} and TCR{gamma} repertoires in a real-world cohort of patients with advanced RCC treated predominantly with first-line immune checkpoint inhibitor-based regimens. Responders exhibited a significantly more even TCR{beta} repertoire together with increased TCR{gamma} diversity and clonal richness, whereas non-responders showed greater TCR{gamma} clonal dominance. In addition, the preferential usage of specific TRBV genes, including TRBV5.7, TRBV7.1, and TRBV18, was associated with clinical response and longer progression-free survival. In this exploratory cohort, integration of the most informative TCR{beta} and TCR{gamma} variables into a combined random forest model yielded an area under the receiver operating characteristic curve of 0.90 in leave-one-out cross-validation, with 100% sensitivity and 81.8% specificity at the selected threshold. To our knowledge, this is the first study to simultaneously characterize baseline intratumoral TCR{beta} and TCR{gamma} repertoires in patients with advanced RCC predominantly receiving first-line immune checkpoint blockade. These findings support baseline intratumoral TCR repertoire features as candidate tissue biomarkers for pretreatment patient stratification and provide a rationale for the prospective validation of TCR repertoire profiling as a predictor of immunotherapy benefit in RCC.
ER -