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PD-1 blockade induces responses by inhibiting adaptive immune resistance

Paul C. Tumeh, Christina L. Harview, Jennifer H. Yearley, Et al.

Nature 515, 568–571 (27 November 2014)

Editor's comments:
The up-regulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8+ T cells is one of the mechanisms by which cancer tissues limit the host immune response. PD-L1 expressed by cancer cells in the tumor microenvironment, binding to PD-1 on T cells can block effector functions and reduce T-cell killing capacity. PD-L1 can be constitutively expressed on the surface of cancer cells or expressed in response to T cells producing immune-stimulating cytokines such as interferons. This process has been termed adaptive immune-resistance and represents a mechanism by which cancer cells attempt to protect themselves from immune-cell-mediated killing Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. This article highlighted the central role played by the CD8 + cells in predicting response to these treatments. Considering the central role played by the effector T cell in the induced expression of PD-L1 in the tumor microenvironment, and being known that the PD-L1 expression correlates with responses to PD1/PD-L1 inhibitors, the authors analyzed the correlation between CD8+ T cells presence in the collected tumor samples and response to treatment. Analyzing different samples obtained from 46 patients with metastatic melanoma treated with pembrolizumab, the authors have shown that the presence of pre-existing CD8 + cells at the invasive tumor margin is associated with the expression of PD-L1 and correlates with the response to treatment. In addition, in patients who showed a response to treatment, radiological density of CD8 + increased from baseline to post-dosing biopsy. This findings indicate that response to PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance. 

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types1, 2, 3, 4, 5. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8+ T cells (termed adaptive immune resistance)6, 7. Here we show that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.