Neutrophils negatively correlate with response to anti-PD-1 monotherapy in dMMR tumours

Responses to treatment with anti-PD-(L)1 therapy vary across different mismatch repair deficient (dMMR) tumours. Local inhibitory effects of neutrophils were associated with a poor response.

Clinical studies have highlighted the efficacy of anti-PD-(L)1 treatment in patients with hypermutated microsatellite instability-high (MSI-H) or dMMR tumours. However, the responsiveness of MSI-H/dMMR tumours to anti-PD-(L)1 treatment is variable. To get more insight in the cause of this variability of response, investigators generated two mouse tumour cell lines inactivated for MSH2 (4T1^MSH2-/- and CT26^MSH2-/-) to recapitulate the MSI-H/dMMR phenotype. Dr Laetitia Nebot-Bral (Institute Gustave Roussy, France) presented the first results [1].

While anti-PD-1 treatment was effective in the CT26 model, no efficacy was observed in the 4T1 model, even in ultra-mutated 4T1 tumours (>280 mutations/Mb). Unlike the CT26 model, the 4T1 model is characterised by an accumulation of neutrophils. In addition, neutrophil depletion with the antibody αLy6G restored the response of 4T1 tumours to anti-PD-1. The combination of anti-PD-1 and anti-CTLA-4 was also able to restore the response to immunotherapy in the 4T1 model.

“Given that the combination treatment was accompanied by a decrease in neutrophils, it is likely that CTLA-4 blockade may hamper the accumulation of neutrophils,” suggested Dr Nebot-Bral.

Based on these results, Dr Nebot-Bral concluded that “accumulation of neutrophils is associated with resistance to anti-PD-(L)1 monotherapy in MSI-H/dMMR tumours. We propose that anti-PD-1 plus anti-CTLA-4 combination therapy may represent an effective strategy in patients with abnormal neutrophil accumulation.”

1. Nebot-Bral L, et al. Neutrophils are associated with resistance to anti-PD-1 monotherapy in mismatch repair-deficient tumors. Abstract 1801MO, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November, 202115 February, 2024