PD-1 blockade induces responses by inhibiting adaptive immune resistance

Abstract

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.1–5 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 analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR). In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, 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 following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance.

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…A limiting factor in immune therapy is the insufficient homing of T cells to the tumor site. Many of the new immune therapies either require the presence of pre-existing T cells in the tumor, 12 , 26 , 27 or rely on sufficient tumor homing of tumor specific T cells after peripheral or in vitro activation. 14 , 28 …”

“…10 This is supported by accumulating data linking response to immune therapy with a brisk infiltration of T cells in the tumor. 7 , 11 , 12 …”

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

“…38 Hence, the mechanism of action of anti-PD-1 therapy is to reverse the exhaustion of pre-existing tumor-residing T cells, thus improving their effector functions to carry out tumor regressions. 39–41 Depending on the context and their sensitivity, if tumor-infiltrating T cells undergo adequate exposure to corticosteroids, then the benefits conferred by anti-PD-1 therapy may be diminished or completely lost. Endogenous and exogenous corticosteroids have been demonstrated to reduce antitumor immunity and counteract cancer immunotherapy in a murine autochthonous pancreatic ductal carcinoma model.…”

T‐cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death‐ligand 1 expression in patients with soft tissue sarcomas

“…How to best select patients, design combination strategies, and sequence regimens are areas of intense research that will hinge on an improved understanding of the tumor immune microenvironment. Approaches to interrogate the tumor microenvironment have included characterization of infiltrating immune cells, immunohistochemistry (IHC) to quantify the expression of inhibitory molecules including programmed death‐ligand 1 (PD‐L1), characterization of the lymphocyte infiltrates using T‐cell receptor Vβ gene (TCR‐Vβ) sequencing, and gene expression analysis 10, 11, 12. However, few studies in any cancer type have used multiple modalities to understand how these different elements interact with one another.…”