ICOS-Mediated T Cell Co-Stimulation in Cancer Immunotherapy

Inducible co-stimulation via the ICOS pathway is a key mechanism by which activated T cells receive signals that enhance proliferation, survival and effector functions. Engagement of ICOS on T cells by its ligand (ICOS-L) on antigen-presenting cells triggers intracellular pathways that support Th1 and Th2 differentiation, promote cytokine secretion and shape memory responses. In the cancer setting, ICOS expression is induced upon checkpoint blockade or other immune-activating therapies, and ICOS–ICOS-L interactions can influence the balance between effector T cells, regulatory T cells and myeloid subsets within the tumour microenvironment. Strategies to exploit the ICOS axis in immunotherapy include agonistic antibodies, gene-modified vaccines and oncolytic viruses engineered to express ICOS-L, all of which aim to amplify antitumour T-cell responses. Ongoing research has illuminated the structural basis of receptor–ligand binding, the interplay with other checkpoints, and the impact of tumour-intrinsic ICOS modulation on clinical outcomes, underlining the broad potential of targeting this co-stimulatory pathway in combination regimens.

Research from Nature Portfolio

Structural studies have resolved the ICOS–ICOS-L complex at atomic resolution, revealing the FDPPPF motif and N-glycan contacts that govern specificity and affinity. This high-resolution map has demonstrated how therapeutic antibodies can mimic natural interactions and informed the design of agonists that precisely engage the ICOS interface. Parallel work has uncovered an unconventional role for osteopontin as a secondary ligand for ICOS-L, showing that its binding can promote angiogenesis and metastasis in vivo. These findings have broadened the conceptual framework around ICOS-L function and highlighted alternative targets within the co-stimulatory network for therapeutic intervention.

ICOS-Mediated T Cell Co-Stimulation in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in icos-mediated t cell co-stimulation in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

ICOS (Inducible T-cell Co-Stimulator): A receptor on activated T cells that delivers positive co-stimulatory signals upon binding to ICOS-L.

ICOS-L (ICOS Ligand): The cognate ligand for ICOS, expressed on antigen-presenting and tumour cells.

Co-stimulation: A secondary signal required by T cells, in addition to T-cell receptor engagement, to fully activate and avoid anergy.

Tumour Microenvironment (TME): The complex milieu of malignant cells, immune infiltrates, stromal elements and soluble factors surrounding a tumour.

DNA Methylation: An epigenetic modification that can regulate gene expression through the addition of methyl groups to cytosine bases.

Oncolytic Virus: A genetically engineered or naturally occurring virus that selectively infects and kills cancer cells while stimulating immune responses.

References

1. ICOS DNA methylation regulates melanoma cell-intrinsic ICOS expression, is associated with melanoma differentiation, prognosis, and predicts response to immune checkpoint blockade. Biomarker Research (2023).
2. ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype. Journal of Experimental Medicine (2024).
3. Inducing expression of ICOS-L by oncolytic adenovirus to enhance tumor-specific bi-specific antibody efficacy. Journal of Translational Medicine (2024).
4. Osteopontin binds ICOSL promoting tumor metastasis. Communications Biology (2020).
5. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nature Communications (2020).