Copper(II)-catalyzed preparation of alkylindium compounds and applications in cross-coupling reactions both in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2019.151288

An efficient water-based method for the synthesis of alkylindium compound in the presence of a catalytic amount of cheap and readily available CuSO₄·5H₂O (10 mol%) was developed. The thus-generated alkylindium compounds effectively underwent palladium-catalyzed cross-coupling reactions with a myriad of aryl halides in aqueous media, leading to the cross-coupled products in modest to high yields. The mildness of the formed alkyl organometallics allowed the tolerance to various important functional groups incorporated in both substrates of alkyl iodides and aryl halides.

Full text of DOI:10.1016/j.tetlet.2019.151288

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