Immune Checkpoint Modulation in Colorectal and Esophageal Cancers

Immune checkpoints are key modulators of T-cell activity, preventing excessive immune responses but also enabling tumour cells to evade immune surveillance. In colorectal cancer (CRC), blockade of PD-1 or PD-L1 has revolutionised treatment for the subset of patients with microsatellite-instable, hypermutated tumours, yet the majority of CRCs remain mismatch-repair proficient and derive limited benefit. Esophageal squamous cell carcinoma (ESCC) similarly exhibits heterogeneity in checkpoint ligand expression, with a proportion of cases showing upregulation of PD-L1 in tumour cells and infiltrating immune cells. Recent advances have combined checkpoint inhibition with other modalities—such as radiotherapy, targeted kinase inhibition or microenvironment-modulating agents—to overcome primary resistance. Detailed mapping of checkpoint molecules and immune subsets within tumour niches has revealed spatial patterns that correlate with prognosis and may inform patient selection. Ongoing efforts aim to refine biomarker panels and optimise combination strategies to extend durable responses beyond current responder groups in both CRC and ESCC.

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Immune Checkpoint Modulation in Colorectal and Esophageal Cancers publication trend

The graph below shows the total number of articles in immune checkpoint modulation in colorectal and esophageal cancers across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint: A regulatory pathway in the immune system that downregulates T-cell activity to maintain self-tolerance and limit collateral tissue damage, which can be co-opted by tumours to escape immune attack.

PD-1 (programmed death-1): An inhibitory receptor on activated T cells that, upon binding to its ligands, attenuates T-cell proliferation and cytokine production.

PD-L1 (programmed death-ligand 1): A ligand for PD-1 expressed by tumour cells and certain immune subsets that delivers inhibitory signals to T cells and contributes to immune evasion.

CTLA-4 (cytotoxic T-lymphocyte-associated protein 4): An immune checkpoint receptor on T cells that primarily regulates early activation events in lymphoid organs.

Tumour microenvironment (TME): The complex milieu surrounding a tumour, including stromal cells, immune infiltrates, vasculature and extracellular matrix, which collectively influence tumour behaviour and treatment response.

Microsatellite instability (MSI): A hypermutable phenotype resulting from deficient DNA mismatch repair, leading to high neoantigen burden and increased sensitivity to immune checkpoint blockade.

References

1. Spatially resolved multimarker evaluation of CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint expression and macrophage polarisation in colorectal cancer. British Journal of Cancer (2023).
2. Radioimmunotherapy in colorectal cancer treatment: present and future. Frontiers in Immunology (2023).
3. Immuno-Contexture and Immune Checkpoint Molecule Expression in Mismatch Repair Proficient Colorectal Carcinoma. Cancers (2023).
4. Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma. Oncotarget (2016).