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Cancer Institute Seminar Series - Dr Alejandro Jimenez

13 December 2018, 12:00 pm–1:00 pm

Ovarian tumour microenvironment

Dr Alejandro Jimenez, Cambridge University, presents: 'Characterisation of the tumour microenvironment in Ovarian Cancer.'

Event Information

Open to

All

Organiser

Veronica Dominguez

Location

Courtyard Cafe
UCL Cancer Institute
72 Huntley Street
London
WC1E 6DD

Hosted by Dr Nicholas McGranahan

In metastatic cancer, the role of heterogeneity at the tumor-immune microenvironment, its molecular underpinnings and clinical relevance remain largely unexplored. To understand tumor-immune dynamics at baseline and upon chemotherapy treatment, we performed unbiased pathway and cell type-specific immunogenomics analysis of treatment-naive (38 samples from 8 patients) and paired chemotherapy treated (80 paired samples from 40 patients) high-grade serous ovarian cancer (HGSOC) samples. Whole transcriptome analysis and image- based quantification of T cells from treatment-naive tumors revealed ubiquitous variability in immune signaling and distinct immune microenvironments co-existing within the same individuals and within tumor deposits at diagnosis. To systematically explore cell type composition of the tumor microenvironment using bulk mRNA, we derived consensus immune and stromal cell gene signatures by intersecting state-of-the-art deconvolution methods, providing improved accuracy and sensitivity when compared to HGSOC immunostaining and leukocyte methylation data sets. Cell-type deconvolution and pathway analyses revealed that Myc and Wnt signaling associate with immune cell exclusion in untreated HGSOC. To evaluate the effect of chemotherapy on the intrinsic tumor-immune heterogeneity, we compared site- matched and site-unmatched tumors before and after neoadjuvant chemotherapy. Transcriptomic and T-cell receptor sequencing analyses showed that site-matched samples had increased cytotoxic immune activation and oligoclonal expansion of T cells after chemotherapy, which was not seen in site-unmatched samples where heterogeneity could not be accounted for. These results demonstrate that the tumor-immune interface in advanced HGSOC is intrinsically heterogeneous, and thus requires site-specific analysis to reliably unmask the impact of therapy on the tumor-immune microenvironment.

This seminar has been sponsored in part by the Biomedical Research Centre and Cancer Research UK.

A light lunch will be served after the seminar. 

Image: Ovarian Tumor Microenvironment National Cancer Institute \ Comprehensive Cancer Center of Wake Forest Univ. Chris Booth, Kyle Cowdrick, Frank C. Marini