Multi-omics strategies with a focus on discovering novel immuno-modulatory targets in prospective and retrospective cohorts of gynaecological cancer patients

Abstract

There is still a significant portion of gynaecological cancer patients that do not respond well to immune-based cancer therapies. Results of a phase II clinical trial demonstrated the efficacy of the PD-1 inhibitor in advanced cervical cancer which led to Food and Drug Administration (FDA) approval. However, 5-year relative survival for these patients is still less than 20%. In ovarian cancer, the rationale behind the use of immune-oncological treatments is that many tumours demonstrate tumour infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, early clinical trials have showed that immune checkpoint inhibitors efficacy remains limited with response rate of 10-15%. Therefore, identifying immune-modulatory targets that could be used to develop novel immune-oncology based therapeutics for cervical and ovarian cancer patients is of great clinical interest. The effectiveness of the tumour immune response is driven by the balance between inflammatory networks, cell exhaustion, and down-modulatory networks which directly influences tumour growth, metastasis, and relapse. This project aims to identify new molecules, pathways, cells or networks that are relevant for the modulation of anti-tumour immune responses. We will investigate the immune tumour microenvironment (TME) in prospective and retrospective cohorts of cervical (n = 40 - 60) and ovarian (n = 20 - 50) cancers comparing patients with good vs. poor outcomes to therapy. Our group recently demonstrated that immune TMEs rich in CD3+ T cells and B cells are predictive of better overall survival in oral cavity cancer, and that CD3+ T cells served as an independent prognostic marker. Lung cancer studies from our laboratory also showed that peripheral blood cell subpopulations are able to predict response to therapy in a cohort of patients treated with chemotherapy and anti-PD1. Thus, the comparison between cell populations identified in the blood vs. those in the TME can aid in identification of potentially important targets for driving effective anti-tumour immune responses vs. the establishment of an inhibitory TME and down-modulation of anti-tumour responses. Prospective analyses of peripheral blood and tumour biopsies/fragments collected at different time points using flow cytometry, scRNAseq and bead array will elucidate the cellular and soluble immune profile in the blood, as well as the TME immune profile. Whereas the retrospective analyses will rapidly identify immune targets related to treatment response effectiveness through multiplex fluorescence and transcriptome/exome sequencing. In addition, we will perform longitudinal studies and correlate the peripheral immune response with the local TME and clinical outcomes (survival, disease recurrence, etc) which will allow the identification of companion biomarkers that may predict which patient will most benefit from potential new therapeutics. Multi-omics targets identified in this project will be further validated in preclinical studies. (AU)