Immune Checkpoint Inhibition in Pediatric Oncology

Immune checkpoint inhibitors (ICIs) represent a transformative class of therapies that unleash antitumour T-cell responses by blocking regulatory receptors such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). In paediatric oncology, the distinct biology of childhood cancers poses both challenges and opportunities. Many paediatric tumours display low mutational burden and limited neoantigen diversity, resulting in an immunologically “cold” microenvironment with few infiltrating CD8+ T cells. Conversely, rare hypermutant cancers driven by mismatch repair deficiency or polymerase proofreading defects can exhibit high mutation loads and pronounced immune infiltration, making them particularly amenable to PD-1 blockade. Preclinical studies have shown that combining checkpoint inhibitors with strategies to modulate suppressive myeloid cells or deplete regulatory CD4+ subsets can overcome resistance in models such as neuroblastoma. Clinically, phase I and II trials have begun to establish safety and preliminary efficacy, while ongoing research seeks robust biomarkers to predict response, optimise dosing and manage immune-related adverse events in growing patients. As understanding of tumour genetics and microenvironmental factors deepens, ICIs are poised to become an integral component of multimodal paediatric cancer care.

Research from Nature Portfolio

Genomic profiling studies have demonstrated that children with germline mismatch repair deficiency or polymerase proofreading defects harbour exceptionally high mutation burdens and microsatellite indels, correlating with durable responses to PD-1 blockade even in central nervous system tumours. These findings underscore the dual predictive roles of overall mutation load and microsatellite-indel frequency in selecting candidates for checkpoint inhibition. In preclinical neuroblastoma models, the concurrent blockade of PD-1/PD-L1 and transient CD4+ T-cell depletion achieved synergistic CD8+-dependent tumour regression and long-term immunity, illustrating the importance of targeting both adaptive resistance and regulatory subsets. Detailed immunohistochemical analyses of embryonal rhabdomyosarcoma revealed low overall lymphocyte infiltration but identified CD163+ macrophages and CD54+ microvessels as prognostic markers, informing strategies to remodel the tumour microenvironment to enhance checkpoint efficacy.

Immune Checkpoint Inhibition in Pediatric Oncology publication trend

The graph below shows the total number of articles in immune checkpoint inhibition in pediatric oncology across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint: A regulatory pathway that maintains self-tolerance by inhibiting T-cell activity, often exploited by tumours to evade immune attack.

PD-1 (programmed cell death-1): An inhibitory receptor on T cells that, upon binding its ligands, dampens effector functions and promotes immune tolerance.

CTLA-4 (cytotoxic T-lymphocyte antigen-4): A T-cell surface molecule that competes with the costimulatory receptor CD28, attenuating early T-cell activation.

Tumour mutation burden (TMB): The total number of somatic mutations per megabase of tumour DNA, used as a surrogate for neoantigen load.

Mismatch repair deficiency (MMRD): A genomic defect impairing DNA repair, leading to microsatellite instability and high mutational burden.

Tumour microenvironment (TME): The cellular milieu surrounding tumour cells, including immune, stromal and vascular components that influence therapy response.

Neoantigen: A novel peptide arising from tumour-specific mutations that can be presented on MHC molecules to T cells.

References

1. Safety and clinical efficacy of sintilimab (anti-PD-1) in pediatric patients with advanced or recurrent malignancies in a phase I study. Signal Transduction and Targeted Therapy (2023).
2. A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer. Genome Medicine (2023).
3. Efficacy of nivolumab in pediatric cancers with high mutation burden and mismatch-repair deficiency. Clinical Cancer Research (2023).
4. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency. Nature Medicine (2022).
5. Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade. OncoImmunology (2016).
6. CD163+ immune cell infiltrates and presence of CD54+ microvessels are prognostic markers for patients with embryonal rhabdomyosarcoma. Scientific Reports (2019).
7. Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma. Scientific Reports (2017).