Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge
Melanomas that responded to pembrolizumab already contained killer T cells pressed up against tumour cells expressing PD-L1, showing that the drug works by releasing an immune attack that is already there rather than creating a new one.
Overview
Tumeh, Ribas and colleagues at UCLA studied tumour biopsies from 46 patients with metastatic melanoma before and during pembrolizumab. Responding tumours had higher densities of CD8 T cells, PD-1 and PD-L1 at the invasive margin and in the tumour before treatment, with T cells and PD-L1 in close proximity, and their T cell receptor repertoires were more clonal and expanded further on treatment. The authors proposed that PD-L1 is induced as an adaptive resistance mechanism in response to interferon from attacking T cells and that pembrolizumab reverses it.
- Serial biopsies from 46 melanoma patients treated with pembrolizumab.
- Pre-treatment CD8 T cell density and PD-1 and PD-L1 expression at the invasive margin and in the tumour were higher in responders.
- Responders showed more clonal T cell receptor repertoires that expanded during treatment.
- A predictive model based on these features identified most responders in a validation set.
This paper explained why PD-1 antibodies work in some patients and not others and introduced the idea of inflamed versus non-inflamed tumours that now guides combination strategies designed to bring T cells into cold tumours.
- Small cohort from a single centre.
- Biopsies sample one site and may not represent all metastases.
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