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

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway offer therapeutic benefits in various cancers, including metastatic urothelial cancer.
• However, only a subset of patients respond to these treatments, necessitating research into resistance mechanisms.
• Understanding the factors influencing response and resistance is crucial for optimizing cancer immunotherapy strategies.

Purpose of the Study:

• To identify key determinants of response and resistance to anti-PD-L1 therapy in metastatic urothelial cancer.
• To investigate the role of transforming growth factor β (TGFβ) signaling in mediating resistance.
• To explore combination strategies involving TGFβ blockade and anti-PD-L1 antibodies in a preclinical model.

Main Methods:

• Analysis of tumor samples from a cohort of metastatic urothelial cancer patients treated with atezolizumab (anti-PD-L1).
• Assessment of CD8+ T-cell phenotype, neoantigen/tumor mutation burden, and TGFβ signaling signatures.
• Utilizing a mouse model mimicking immune exclusion to test combination therapy.

Main Results:

• Treatment response correlated with CD8+ T-effector cell phenotype and high tumor mutation burden.
• Resistance was associated with TGFβ signaling in fibroblasts and an immune-excluded phenotype.
• Combination therapy in a mouse model reduced TGFβ signaling, enhanced T-cell infiltration, and promoted tumor regression.

Conclusions:

• TGFβ signaling in the tumor microenvironment restrains anti-tumor immunity by limiting T-cell infiltration.
• Targeting TGFβ in conjunction with PD-L1 blockade represents a promising strategy to overcome resistance in urothelial cancer.
• Integrating T-cell phenotype, tumor mutational burden, and TGFβ pathway activity offers a comprehensive approach to predicting patient outcomes.