TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
By S. Mariathasan, S. Turley, D. Nickles, A. Castiglioni, Kobe Yuen, Yulei N. Wang, E. Kadel, H. Koeppen, Jillian L Astarita, R. Cubas and 32 more. Nature, 2018
4,528 citations recorded by the source corpus.
Therapeutic antibodies that block the programmed death-1 (PD-1)–programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. 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 patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.
View Paper: https://www.semanticscholar.org/paper/d15b46b3145c39f89c96b72cd641e3b628322cda
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In Oncology
Citations in the corpus
- TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis (2019, positive): “595 Finally, an interesting paper showed that a TGF-β inhibitor in combination with a PD-L1 596 inhibitor (Atezolizumab) may be able to remodel the matrix microenvironment and allow T cells to 597 enter the interior of the tumor [237].”
- Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer (2021, background): “Meanwhile, the combination of TGF-β blockers and anti-PD-L1 antibodies promoted T cell penetration into the tumor center, improving tumor responsiveness to anti-PD-L1 therapy.(328) Activated CAFs can also produce TGF-β to form a positive-feedback loop for CAFs activation.”
- Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “In this regard, two studies showed recently that the TGF-β blocking increases the therapeutic response of anti-PDL1 therapy, resulting in tumor regression in EMT6 breast carcinomamodels (Mariathasan et al. 2018) and complete elimination of established livermetastases froma colorectal cancer model (T”
- The role of collagen in cancer: from bench to bedside (2019, background): “However, others noted that the metastatic urothelial cancer response to programmed death-1 and programmed death-ligand 1 treatment involved the movement of CD8+ T cells from the cancer parenchyma to the collagen-rich peritumoral stroma [127].”
- Targeting TGF-β signal transduction for fibrosis and cancer therapy (2022, background): “Coadministration of TGF-β blocking agents and anti-PD-L1 antibodies indicated a dramatic response by promoting CD8 + T cells penetration into the tumor [189].”