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Mutational intensity influences a tumour's response to PD-1 immunotherapy

Following FDA approval last year of PD-1 immune checkpoint inhibitors for tumours with mismatch repair deficiency, a new study reveals more about why responses of these tumours to this immunotherapy vary, specifically implicating mutation intensity.

The findings were published in Science.

The results, from both experimental and clinical studies, provide critical mechanistic insight that may help doctors practice oncology in a more specific way, says author Timothy A. Chan, in a related video. It would allow them to better identify which patients could experience the greatest benefit from anti-PD-1 therapy.

Mismatch repair deficient (MMR-d) tumours can be characterised by high microsatellite instability (MSI ), which can lead to the accumulation of thousands of genomic mutations.

Previous research has shown that the high mutational load of these tumours makes them particularly vulnerable to PD-1 immunotherapy.

However, while PD-1 immunotherapy has demonstrated success in many patients with MSI/MSR-d tumours, clinical outcomes can vary widely and nearly half of these patients fail to respond to anti-PD-1 treatment at all.

The underlying cause of these variable responses is largely unknown.

To address this question, Rajarsi Mandal and colleagues developed mouse models of MSI tumours to compare varying degrees of MSI, or MSI intensity, and its impact on anti-PD-1 response.

The results suggest that the genome-wide intensity of MSI and resulting mutational load, particularly insertion-deletion mutations, play a critical role in both the evolution of MMR-d tumours as well as their individual response to PD-1 immunotherapy.

In addition, using clinical data from human cancer patients with MSI tumours, Mandal et al. discovered similar relationships between MSI intensity and a patient's response to anti-PD-1 therapy.

This study provides rationale for the genome-wide characterisation of MSI intensity and mutational load to better profile responses to PD-1 immunotherapy across MMR-deficient human cancers, the authors say.

Source: American Association for the Advancement of Science

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European Cancer Organisation European Institute of Oncology

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