Abstract

In metastatic cancer, the role of heterogeneity at the tumour-immune microenvironment (TME) interface and its clinical relevance remain largely unexplored. Recently, we showed that distinct TMEs can co-exist within the same individual (Jimenez-Sanchez et al, 2017, Cell). However, the generalizability of this principle, its molecular underpinnings, and the interaction between chemotherapy and the TME remain poorly understood. To understand tumour-immune dynamics at baseline and after chemotherapy, we performed unbiased pathway and cell type-specific immunogenomics analysis of treatment-naive and paired chemotherapy treated high-grade serous ovarian cancer (HGSOC) samples. In treatment-naive tumours we find pervasive variability in immune infiltration confirming the co-existence of distinct TMEs within the same individuals. Further, we find specific oncogenic signalling programmes, e.g. Myc and Wnt, are associated with immune cell exclusion in untreated HGSOC. To evaluate interactions between the TME and chemotherapy, we compared site-matched and site-unmatched tumours before and after neoadjuvant chemotherapy. We find that chemotherapy induces cytotoxic immune activation and oligoclonal expansion of T cells, an effect only seen in site-matched samples. I will discuss these and other unpublished results demonstrating that the TME in advanced HGSOC is intrinsically heterogeneous and thus requires site-specific analysis to reliably unmask chemotherapy’s impact on the TME.