ICOS blockade alleviates immune suppression in breast tumor microenvironment
- 1School of Cancer Medicine, La Trobe University, Bundoora Vic 3086, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg Vic 3084, Australia
Abstract
Immune checkpoint blockade has become a standard of care for triple-negative breast cancer, yet only around half of patients benefit. Compensatory immunoregulatory pathways may limit the efficacy of PD-1/PD-L1 blockade. ICOS, an inducible co-stimulatory receptor enriched on activated regulatory T cells (Tregs), represents a potential route of such immune regulation, but its role in breast cancer immunotherapy remains unclear. Here, we identify ICOS as selectively upregulated on tumor-infiltrating Tregs and show that ICOS Tregs localize within a tumor niche enriched for exhausted CD8 T cells. We confirmed this cellular and spatial association across 1,359 tumor regions from 279 triple-negative breast cancer patients profiled by imaging mass cytometry, and single-cell transcriptomic data from 129 breast cancer donors. Genetic ablation or pharmacological blockade of ICOS disrupted this intratumoral Treg niche, reducing Treg activation and tissue-residency programs while expanding cytotoxic CD8 T cells with a tissue-resident memory phenotype. In syngeneic orthotopic breast cancer models, ICOS blockade restricted primary tumor growth, reduced spontaneous metastasis and prolonged survival without disrupting systemic immune homeostasis. Therapeutic activity was observed with both neoadjuvant and adjuvant treatment, while combined ICOS and PD-1 blockade further enhanced tumor control. These findings support ICOS blockade as a therapeutic strategy to improve checkpoint immunotherapy.
Related
- Stabilizing the CHI3L1-Gal3BP complex remodels the glioblastoma immune microenvironment and synergizes with PD-1 blockade
- Immune checkpoint blockade activates macrophages and remodels the lymph node microenvironment in melanoma metastasis
- Selective estrogen receptor degraders and their effect on the breast cancer immune microenvironment
- Expression, prognostic association, and immune microenvironment correlates of C4orf50 in breast cancer: a The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) bioinformatics study
- A tumor-responsive nanoplatform orchestrating multiplexed macrophage engagers and immune checkpoint blockade for triple-negative breast cancer immunotherapy
BibTeX
@misc{guleria2026icos,
title = {{ICOS blockade alleviates immune suppression in breast tumor microenvironment}},
author = {S. Guleria and C. D. Liyanage and W. J. Hutchison and K. Treller and L. Neil and Y. Gao and B. Yeo and J. M. Mariadason and A. Kallies and C. J. Kearney and L. A. Mielke and S. Vodala and R. L. Anderson and D. Merino and A. T. Papenfuss and V. K. Yadav and A. Vasanthakumar and S. Mangiola and B. Pal},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.760908},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760908v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - ICOS blockade alleviates immune suppression in breast tumor microenvironment
AU - S. Guleria
AU - C. D. Liyanage
AU - W. J. Hutchison
AU - K. Treller
AU - L. Neil
AU - Y. Gao
AU - B. Yeo
AU - J. M. Mariadason
AU - A. Kallies
AU - C. J. Kearney
AU - L. A. Mielke
AU - S. Vodala
AU - R. L. Anderson
AU - D. Merino
AU - A. T. Papenfuss
AU - V. K. Yadav
AU - A. Vasanthakumar
AU - S. Mangiola
AU - B. Pal
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.760908
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.760908v1
AB - Immune checkpoint blockade has become a standard of care for triple-negative breast cancer, yet only around half of patients benefit. Compensatory immunoregulatory pathways may limit the efficacy of PD-1/PD-L1 blockade. ICOS, an inducible co-stimulatory receptor enriched on activated regulatory T cells (Tregs), represents a potential route of such immune regulation, but its role in breast cancer immunotherapy remains unclear. Here, we identify ICOS as selectively upregulated on tumor-infiltrating Tregs and show that ICOS Tregs localize within a tumor niche enriched for exhausted CD8 T cells. We confirmed this cellular and spatial association across 1,359 tumor regions from 279 triple-negative breast cancer patients profiled by imaging mass cytometry, and single-cell transcriptomic data from 129 breast cancer donors. Genetic ablation or pharmacological blockade of ICOS disrupted this intratumoral Treg niche, reducing Treg activation and tissue-residency programs while expanding cytotoxic CD8 T cells with a tissue-resident memory phenotype. In syngeneic orthotopic breast cancer models, ICOS blockade restricted primary tumor growth, reduced spontaneous metastasis and prolonged survival without disrupting systemic immune homeostasis. Therapeutic activity was observed with both neoadjuvant and adjuvant treatment, while combined ICOS and PD-1 blockade further enhanced tumor control. These findings support ICOS blockade as a therapeutic strategy to improve checkpoint immunotherapy.
ER -