Abstract
TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin αV subunit. The activation of latent TGF-β by cancer-cell-expressed αV re-shapes the tumour microenvironment, and this could affect patient responses to PD-1-targeting therapy. Here we show, using multiplex immunofluorescence staining in cohorts of anti-PD-1 and anti-PD-L1-treated lung cancer patients, that decreased expression of cancer cell αV is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8+CD103+ tumour-infiltrating lymphocytes. Mechanistically, tumour αV regulates CD8 T cell recruitment, induces CD103 expression on activated CD8+ T cells and promotes their differentiation to granzyme B-producing CD103+CD69+ resident memory T cells via autocrine TGF-β signalling. Thus, our work provides the underlying principle of targeting cancer cell αV for more efficient PD-1 checkpoint blockade therapy.
Highlights
TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin αV subunit
To investigate the impact of tumour αV expression on survival in patients with lung cancer, we used a retrospective cohort of 113 patients with treatment-naïve early-stage NSCLC15
We did not find any significant difference in overall survival (OS) of patients bearing αVlow and αVhigh tumours (Fig. 1b), with a hazard ratio (HR) = 1.05, 95% confidence interval (CI) 0.38−2.97, and median OS of 68 months
Summary
TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin αV subunit. The quality of CD8+ tumour-infiltrating lymphocytes (TIL), especially their reactivity toward the cognate target, is directly associated with the efficacy of anti-PD-1 In this regard, expression of PD-1 on CD8+ TIL appeared to define clonally expanded tumour neoantigen-specific T cells detected in cancer patients[9,10]. Human non-small-cell lung cancer (NSCLC) CD103+CD8+ TRM cells frequently express the activation marker CD69 and a panel of T cell inhibitory receptors, including PD-114. They are enriched with tumour-reactive T lymphocytes able to kill autologous tumour cells upon blockade of PD-1 with neutralizing antibodies[15]. CD103+CD8+ TRM expands during anti-PD-1 immunotherapy, and their accumulation in tumours is associated with the improved outcome of anti-PD-(L)1-treated patients[14,18,19]
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