Background
Identifying determinants of response to cancer immunotherapy is critical for extending therapeutic benefit to more patients. Atezolizumab (anti–PD-L1) was approved in the US for the treatment of mUC based on the single-arm Phase II study IMvigor210 (NCT02108652). Here, we examined the biology underlying primary immune escape and responsiveness to anti–PD-L1 in tumor samples of participants of IMvigor210.Methods
RECIST v1.1 objective response was a primary endpoint evaluated in all patients and in PD-L1 expression subgroups on tumor-infiltrating immune cells (SP142 IHC). Exploratory analyses in evaluable pre-treatment tissues included: (i) CD8 IHC analysis to define immune deserts, excluded and inflamed subtypes (ii) whole-transcriptome RNA sequencing to identify pathways associated with response and to perform Lund subtyping, (iii) targeted mutational profiling (FoundationOne) to estimate tumor mutation burden, and (iv) whole-exome sequencing to predict putative neoantigens. EMT6-grafted BALB/c mice treated with anti–TGF-β and/or anti–PD-L1 antibodies were evaluated for tumor growth inhibition.Results
Response was associated with CD8+ T-effector gene expression 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. 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. Conclusions
Pre-existing T-cell immunity and TMB are associated with response to atezolizumab in mUC, whereas TGF-β signaling in the stroma is a negative indicator of response, especially in immune-excluded tumors, a common phenotype of mUC. Integration of these 3 independent biological features provides a strong basis for understanding clinical outcomes.