Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Association of Circulating T Cell and Tumor Microenvironment Profiles with Immune Checkpoint Blockade Outcomes in Sarcoma.
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Rosenbaum Evan, Ehrich Fiona, Yosofvand Mohammad, Bradic Martina, Lee Jasme, Adamow Mathew, Movva Sujana, Kelly Ciara M, Avutu Viswatej, Banks Lauren B, Chan Jason E, Chi Ping, Dickson Mark A, Gounder Mrinal M, Keohan Mary L, Maki Robert G, Reed Damon R, Fuentes Paige, Collins Paige, Desir Rhoena, Reiner Allison, Baranov Oleg, Chernyshov Konstantin, Kotlov Nikita, Subramanian Ajay, Moding Everett J, Qin Li-Xuan, Wong Phillip, Tap William D, Antonescu Cristina R, Panageas Katherine S, Shen Ronglai, D'Angelo Sandra P
Аннотация
PURPOSE: Immune checkpoint blockade (ICB) benefits only a subset of patients with sarcoma. Biomarkers of response and resistance are needed to help guide patient selection.
EXPERIMENTAL DESIGN: We analyzed peripheral blood and tumor samples from patients with sarcoma treated in five ICB-based clinical trials. Baseline peripheral blood mononuclear cells (PBMC) underwent 11-color flow cytometry to define T-cell immunotypes. Baseline tumor tissue underwent RNA sequencing (RNA-seq) to classify tumors into four tumor microenvironment (TME) subtypes using consensus clustering of 29 functional gene expression signatures. Associations between immune features and clinical outcomes were assessed. A deep learning model was applied to baseline hematoxylin and eosin (H&E) slides to detect and quantify lymphoid aggregates in patients with available RNA-seq.
RESULTS: Among 178 patients with PBMC available for analysis, a proliferative (PRO) circulating T-cell immunotype was associated with poorer overall survival (OS) than lymphocyte-activation gene 3 (LAG)- or LAG+ immunotypes. RNA-seq from 67 tumors identified an immune-enriched/nonfibrotic TME subtype associated with a higher response rate, longer progression-free survival, and longer OS compared with immune-enriched/fibrotic, immune-depleted, and fibrotic subtypes. Automated analysis of 48 baseline H&E slides identified lymphoid aggregates in five tumors; four were classified as immune-enriched and two of these responded to ICB.
CONCLUSIONS: Patients with sarcoma and a PRO circulating T-cell immunotype had inferior outcomes to ICB, whereas those with an immune-enriched/nonfibrotic TME had superior outcomes. Automated analysis of H&E slides showed promise in identifying patients with an immune-enriched TME. These findings support the use of a multimodal approach to identify predictors of response to immunotherapy in sarcoma.
EXPERIMENTAL DESIGN: We analyzed peripheral blood and tumor samples from patients with sarcoma treated in five ICB-based clinical trials. Baseline peripheral blood mononuclear cells (PBMC) underwent 11-color flow cytometry to define T-cell immunotypes. Baseline tumor tissue underwent RNA sequencing (RNA-seq) to classify tumors into four tumor microenvironment (TME) subtypes using consensus clustering of 29 functional gene expression signatures. Associations between immune features and clinical outcomes were assessed. A deep learning model was applied to baseline hematoxylin and eosin (H&E) slides to detect and quantify lymphoid aggregates in patients with available RNA-seq.
RESULTS: Among 178 patients with PBMC available for analysis, a proliferative (PRO) circulating T-cell immunotype was associated with poorer overall survival (OS) than lymphocyte-activation gene 3 (LAG)- or LAG+ immunotypes. RNA-seq from 67 tumors identified an immune-enriched/nonfibrotic TME subtype associated with a higher response rate, longer progression-free survival, and longer OS compared with immune-enriched/fibrotic, immune-depleted, and fibrotic subtypes. Automated analysis of 48 baseline H&E slides identified lymphoid aggregates in five tumors; four were classified as immune-enriched and two of these responded to ICB.
CONCLUSIONS: Patients with sarcoma and a PRO circulating T-cell immunotype had inferior outcomes to ICB, whereas those with an immune-enriched/nonfibrotic TME had superior outcomes. Automated analysis of H&E slides showed promise in identifying patients with an immune-enriched TME. These findings support the use of a multimodal approach to identify predictors of response to immunotherapy in sarcoma.