Tumour immunology and metabolic immunotherapy

Programme stream(s): Cancer discovery / underpinning research , Treatment

Chair: Susan Critchlow, Astrazeneca, UK
Presenter: Marta Canel, University of Edinburgh, UK
Speaker: Martin Miller, CRUK Cambridge Institute, UK
Speaker: Saverio Tardito, CRUK Beatson Institute, UK
Speaker: Vincenzo Bronte, Federazione Ricerca Biomedica Avanzata Onlus, Italy

4:35 pm-6:35 pm

Room: Lomond Auditorium

The goal of this session is to discuss the cellular and molecular mechanisms that control immune responses with a particular emphasis on how metabolism regulates immune cell function. The session will cover the role of the tumour microenvironment in the control of anti-tumor immunity.

1. Martin Miller, CRUK Cambridge Institute, UK
2. Marta Canel, University of Edinburgh, UK
3. Susan Critchlow, AstraZeneca, UK
4. Saverio Tardito, CRUK Beatson Institute, UK

T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumour immunity.
Speaker: Marta Canel
Affiliation: University of Edinburgh


Focal Adhesion Kinase is emerging as a potentially important regulator of the immuno-suppressive tumour environment in multiple tumour types, and as a consequence FAK inhibitors are now undergoing clinical testing in combination with anti-PD1 immune checkpoint inhibitors. However, which patients are most likely to benefit from FAK inhibitor treatment, and what the optimal FAK / immunotherapy combinations are, is currently unknown.


Using a panel of syngeneic transplantable murine cancer cell models we have identified that endogenous and exogenous expression of the immune costimulatory ligand CD80 on the surface of cancer cells correlates with response of tumours to the FAK kinase inhibitor BI853520. Thus, expression of CD80 by cancer cells may represent a novel biomarker for identification of patients more likely to respond to FAK kinase inhibitors.

CD80 is an immune costimulatory ligand that plays a role in T-cell activation through binding the T-cell co-receptor CD28. However, a previous clinical trial testing the safety of a CD28 superagonist reported severe life-threatening toxicity in all patients, suggesting that development of FAK inhibitor / CD28 agonist combinations would not be possible. We therefore set out to test the concept of T-cell costimulation in combination with BI853520 using agonistic antibodies targeting four T-cell costimulatory receptors for which agents are currently in clinical development, namely GITR, CD40, 41BB, and OX40. We observed a significant improvement in the anti-tumour activity of both 41BB and OX40 when used in combination with BI853520. Of particular note, the combination of OX40 + BI853520 resulted in complete regression of all SCC tumours and a significant growth delay of pancreatic tumours that was not observed with either therapy alone.


These studies support the continued development of FAK kinase inhibitors in combination with immunotherapies, and in particular identify FAK / OX40 as a promising candidate for further investigation.

Co-existing Tumour-Immune Microenvironments in Advanced Ovarian Cancer
Speaker: Martin Miller
Affiliation: University of Cambridge


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.