TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

Abstract

Therapeutic antibodies that block the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer (mUC)1–5. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here, we examined tumours from a large cohort of mUC patients treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). Lack of response was associated with a signature of transforming growth factor β (TGF-β) signalling in fibroblasts, particularly in patients with CD8+ T cells that were excluded from the tumour parenchyma and instead found in the fibroblast- and collagen-rich peritumoural stroma—a common phenotype among patients with mUC. Using a mouse model that recapitulates this immune excluded phenotype, we found that therapeutic administration of a TGF-β blocking antibody together with anti–PD-L1 reduced TGF-β signalling in stromal cells, facilitated T cell penetration into the centre of the tumour, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding outcome in this setting and suggests that TGF-β shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T cell infiltration.

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

“…Immune checkpoint blockade is clinically active in about 15% of patients with advanced bladder cancer, in which response is associated with high tumor mutational burden (TMB), the “genomically unstable” luminal subtypes, and infiltration with activated cytotoxic T lymphocytes (Mariathasan et al, 2018; Sharma et al, 2016; Sjödahl et al, 2012). Given the relatively high mutational frequencies observed in SARCs, we characterized the patterns of immune-related gene expression in them (Figure 4).…”

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

“…4 This phenotype can be associated with a TGF-beta signature in bladder cancer. 8 While that presence of Th1 response associates with a PSA decrease on treatment, induction of inhibitory checkpoints was associated with PSA rise on treatment. We found a trend toward a positive correlation between TGFB1 and PSA change (r = 0.465, p = 0.1150).…”

Role of the immunosuppressive microenvironment in immunotherapy

“…Accordingly, expression of immune checkpoint–related molecules by both tumor and stromal cells has been reviewed extensively elsewhere 37 Table 1Mechanisms of immunosuppression in the tumor microenvironmentMediatorMechanism of immunosuppressionReferencesCell surface proteins Programmed death-ligand 1Induce T-cell tolerance/anergy after ligation with programmed cell death protein 1 on T cells37 CTLA-4Inhibit activation of naïve T cells37Enhance regulatory T cell function74 ↓Major histocompatibility complex IAvoid detection by effector CD8 T cells75 ↓FASAvoid FAS ligand–mediated cell killing ↓TRAILAvoid TRAIL-mediated cell killing CD39/CD73Convert extracellular immunostimulatory adenosine triphosphate to immunosuppressive adenosine76Secreted cytokines Transforming growth factor betaInhibit T cell priming and infiltration77Suppress effector cell cytotoxicity47 Vascular endothelial growth factorInhibit dendritic cell maturation78Enhance programmed cell death protein 1/programmed death-ligand 1/2 expression79Enhance interleukin-10 secretion Interleukin-10Inhibit major histocompatibility complex II expression on antigen presenting cells80Suppress M1 cytokine secretion81Suppress iNOS (inducible Nitric Oxide Synthase)82Induce T cell anergy83Metabolic pathways Indoleamine-2,3 dioxygenaseConvert tryptophan to kynurenine55Inhibit T cell proliferation84 AdenosineInhibit T cell proliferation and activation85, 86 HypoxiaInhibit effector T cell function87...…”