New Diagnostic Test Assesses Suitability for Immune Checkpoint Inhibitor Immunotherapy

A newly developed diagnostic procedure enables doctors to predict whether a cancer patient will benefit from immune checkpoint inhibitor immunotherapy.

Checkpoint inhibitor therapy is a form of cancer immunotherapy, which targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from immune attack by stimulating immune checkpoint targets, and checkpoint therapy can block inhibitory checkpoints, restoring immune system function.

PD-1 is the transmembrane programmed cell death 1 protein, which interacts with PD-L1 (PD-1 ligand 1). PD-L1 on the cell surface binds to PD-1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T-cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T-cells that might otherwise attack the cancer cell. Antibodies that bind to either PD-1 or PD-L1, and therefore block the interaction, may allow T-cells to attack the tumor.

While checkpoint inhibitor immunotherapy has proven to be quite successful in some patients, in others it has demonstrated little or no effect. Given the inherent toxicity of these treatments, is necessary to define which patients are most likely to benefit from them, avoiding unnecessary exposure to those who will not. In this regard, investigators at the University of Bath (United Kingdom) addressed the issue of a patient’s suitability for immune checkpoint treatment.

The investigators quantitatively imaged PD-1/PD-L1 interactions in tumor biopsy specimens from patients, employing an assay that readily detected these intercellular protein-protein interactions in the 10 nanometer range. Results of these analyses across multiple patient cohorts demonstrated the inter-cancer, inter-patient, and intra-tumoral heterogeneity of interacting immune checkpoints. While the PD-1/PD-L1 interaction was not correlated with clinical PD-L1 expression scores in malignant melanoma, among anti-PD-1 treated metastatic non-small-cell lung carcinoma (NSCLC) patients, those with lower PD-1/PD-L1 interaction had significantly worsened survival.

Senior author Dr. Banafshé Larijani, director of the Centre for Therapeutic Innovation at the University of Bath, said, "Currently, decisions on whether to proceed with checkpoint inhibitor treatment are based simply on whether PD-1 and PD-L1 are present in biopsies, rather than their functional state. However our work has shown it is far more important to know that the two proteins are actually interacting and therefore likely to be having a functional impact on tumor survival."

The immune checkpoint paper was published in the August 27, 2020, online edition of the journal Cancer Research.

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