Annals of Oncology
abstracts
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875PD Targeting molecular mediators of T cell exclusion for effective
immunotherapy in ovarian cancer
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Y. Wang , M. Desbois , A. Udyavar , L. Ryner , C. Kozlowski , Y. Guan , M. D u¨ rrbaum ,
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S. Lu , J-P. Fortin , H. Koeppen , J. Ziai , C-W. Chang , A. Lo , S. Keerthivasan ,
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M. Plante , C. Bais , P. Hegde , A. Daemen , S. Turley
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Oncology Biomarker, Genentech Inc. - Roche - USA, Foster City, CA, USA, Oncology
Biomarker, Genentech Inc. - Roche - USA, South San Francisco, CA,
USA, Bioinformatics, Genentech Inc. - Roche - USA, Foster City, CA, USA, Pathology,
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Genentech Inc. - Roche - USA, Foster City, CA, USA, Biostatistics, Genentech Inc. -
Roche - USA, Foster City, CA, USA, Research, Genentech Inc. - Roche - USA, Foster City,
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CA, USA, Cancer Research Center, Laval University, Quebec, QC, Canada
Background: Close proximity between cytotoxic T lymphocytes and tumour cells is
required for effective immunotherapy. However, what determines the spatial distribu-
tion of T cells in the tumour microenvironment is not well understood. Coupling digi-
tal pathology and transcriptome analysis on large ovarian tumour cohorts, here we
report classification and functionally dissection of tumour-immune contexture in
human ovarian cancer.
Methods: CD8 IHC and RNAseq analysis were performed on 370 ovarian tumours
from the ICON7 phase III clinical trial. Coupling digital pathology with transcriptome
analysis, a random forest machine learning algorithm was developed and independ-
ently validated for classifying tumour-immune phenotypes in ovarian cancer. Anti-
tumour activity of TGFb blockade in combination with anti-PD-L1 was evaluated in an
ovarian cancer mouse model.
Results: We show the identified tumour-immune phenotypes are of biological and
clinical importance with interconnection to molecular subtypes and association with
clinical outcome in ovarian cancer. Two important hallmarks of T cell exclusion were
identified: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFb
and activated stroma. We identified TGFb as a key mediator of T cell exclusion. TGFb
reduced MHC class I expression in ovarian cancer cells and induced extracellular
matrix (ECM) production and immunosuppressive molecules in human primary
fibroblasts. Finally, we demonstrated that combination of anti-TGFb and anti-PD-L1
in a mouse ovarian cancer model significantly improved the anti-tumour efficacy and
survival.
Conclusions: This study provided the first systematic and in-depth characterization of
the molecular features and mechanisms underlying the tumour-immune phenotypes
in ovarian cancer. We illuminated a multi-faceted role of TGFb in mediating conse-
quential crosstalk between tumour cells and cancer associated fibroblasts to shape the
tumour-immune contexture. Our findings support that targeting the TGFb pathway
represents a promising therapeutic strategy to overcome T cell exclusion and optimize
response to cancer immunotherapy.
Legal entity responsible for the study: The authors.
Funding: Genentech/Roche.
Disclosure: All authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz268 | v761