8O_PR - TGF-_ signalling attenuates tumour response to PD-L1 checkpoint blockade by contributing to retention of T cells in the peritumoural stroma (8O)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Proffered Paper session
Topics Colon Cancer
Rectal Cancer
Gastrointestinal Cancers
Presenter Sanjeev Mariathasan
Authors S. Mariathasan1, S.J. Turley1, D. Nickles1, A. Castiglioni1, K. Yuen1, Y. Wang1, K. Edward E. III1, H. Koeppen1, J.L. Astarita1, R. Cubas1, S. Jhunjhunwala1, Y. Yang1, Y. Şenbabaoğlu1, M. van der Heijden2, Y. Loriot3, I. Mellman1, D. Chen1, P. Hegde1, R. Bourgon1, T. Powles4
  • 1-, Genentech, Inc., 94080 - South San Francisco/US
  • 2-, Netherlands Cancer Institute, - - Amsterdam/NL
  • 3Department Of Cancer Medicine, Institut Gustave Roussy, 94800 - Villejuif/FR
  • 4Barts Cancer Institute, St. Bartholomew's Hospital, EC1A 7BE - London/GB

Abstract

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.

Clinical trial identification