Targeting ICOS to improve breast cancer immunotherapy — ASN Events
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  3. Targeting ICOS to improve breast cancer immunotherapy

Targeting ICOS to improve breast cancer immunotherapy (#105)

Chamikara Liyanage 1 2 , Shalini Guleria 1 2 , William Hutchison 3 , Liam Neil 1 2 , Caroline Bell 1 2 , Raymond Yip 3 4 , John Mariadason 1 2 , Axel Kallies 4 5 , Ajithkumar Vasanthakumar 2 , Belinda Yeo 2 6 , Robin Anderson 1 2 , Stefano Mangiola 3 7 , Bhupinder Pal 1 2
  1. School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
  2. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
  3. The Walter and Eliza Hall Instituteof Medical Research, Parkville, Victoria, Australia
  4. The University of Melbourne, Parkville, Victoria, Australia
  5. The Peter Doherty Institute forInfection and Immunity, Melbourne, Victoria, Australia
  6. Austin Health, Heidelberg, Victoria, Australia
  7. South Australian immunoGENomics Cancer Institute, Adelaide, South Australia, Australia

Background

Immune checkpoint inhibitors (ICIs), such as anti-PD1 therapy, have achieved remarkable success in melanoma and lung cancer but show limited efficacy in breast cancer [1-4]. Tumor infiltration of ICOS-positive (ICOS⁺) regulatory T cells (Tregs) contributes to immune suppression by enhancing PD-1 expression on cytotoxic CD8⁺ T and natural killer (NK) cells. Therefore, blocking the ICOS receptor, which is required for Treg cell activity, could be an effective strategy to reverse the cytotoxic function of immune cells [5, 6]. This study investigates ICOS targeting as a therapeutic strategy in preclinical mammary tumor models.

Methods

Orthotopic syngeneic mammary tumor models (EO771.LMB; hormone receptor-negative) were established in Icos-/- C57BL/6 female mice to understand Icos-driven immunosuppressive mechanisms in breast tumors. The therapeutic efficacy of blocking the Icos receptor was evaluated using monoclonal antibodies in EO771.LMB and 67NR (hormone-receptor positive) models in combination with anti-PD1 therapy. Flow cytometry and single-cell RNA sequencing were used to analyze immune cell modulation. Multiplex immunohistochemistry and spatial transcriptomic analysis of human clinical specimens characterized the cellular and molecular interactions of ICOS+ Tregs in the tumor microenvironment.

Results

Systemic deletion of Icos resulted in a significant reduction in mammary tumor growth, associated with decreased Treg activation and function, and increased infiltration and activity of CD8+ T and NK cells. Moreover, the combination treatment (anti-Icos + anti-PD-1) demonstrated a substantial reduction in mammary tumor burden in both EO771.LMB and 67NR models, indicating synergistic anti-tumor activity through simultaneous depletion of Icos⁺ Treg cells and reinvigoration of exhausted cytotoxic cells. Additionally, combination immunotherapy demonstrated improved metastasis-free survival in both neoadjuvant and adjuvant treatment settings. Spatial-omics data provide a detailed map of ICOS⁺ Treg enrichment in the tumor core, forming immunosuppressive niches with ICOS-Ligand+ cancer cells and exhausted CD8+ T cells.

Conclusions

Pharmacological blockade of the ICOS receptor can suppress Treg-induced immunosuppression, sensitizing breast cancer cells to immunotherapy-driven anti-tumor responses. Hence, an anti-ICOS and anti-PD1 combination may provide a promising therapeutic approach for patients with early-stage or advanced breast cancer. Additionally, integrating ICOS⁺ Tregs into TIL scoring systems would aid in stratifying breast cancer patients for future ICOS-targeted immunotherapy trials.

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  5. Wang, P., Zhang, Q., Zhang, H., Shao, J., Zhang, H. and Wang, Z. Molecular and clinical characterization of ICOS expression in breast cancer through large-scale transcriptome data. Plos one. 2023; 18(12), p.e0293469.
  6. Diamantopoulos, N., Li, J., Bouchard, A., Joumier, L., Mohammaei, S., Panneton, V., Chang, J., Malleshaiah, M. and Suh, W.K. ICOS-expressing Regulatory T Cells Influence the Composition of Antitumor CTL Populations. J Immunol. 2024; 213(5), pp.753-762.