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Page 272 Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18

12. Understanding and exploiting the hypoxia-induced DNA damage response

Ester Hammond

Oxford Institute for Radiation Oncology, UK

Exposure to severe levels of hypoxia, sometime referred to as radiobiological hypoxia, leads to the induc-
tion of the DNA damage response. As cancer cells in radiobiological hypoxia are significantly more resis-
tant to radiation-induced DNA damage they negatively impact radiotherapy response. The aim of our work
is to investigate the biological response and adaption by cancer cells to hypoxia, with the ultimate aim of
developing new therapeutic strategies though the identification of critical molecular targets. Recently, we
have demonstrated that the hypoxia-induced DNA damage response is a result of replication stress, in part
due to diminished ribonucleotide reductase activity in the absence of oxygen. Despite the presence of rep-
lication stress and a DNA damage response in hypoxia, we have not observed the accumulation of DNA
damage. Both the sources of hypoxia-induced replication stress and potential strategies to target this for
therapeutic gain will be discussed.

13. Breaking down barriers to tumour immunity

Awen Gallimore

Cardiff University, UK

Whilst certain immunotherapies can drive activation and expansion of tumour-specific T cells, most pa-
tients undergoing these therapies do not exhibit objective responses. A significant bottleneck may be the fail-
ure of activated lymphocytes to infiltrate solid tumours and/or immunosuppressive mechanisms within the
tumour microenvironment. Foxp3+ regulatory T cells (Treg) often accumulate in solid tumours where they
help create an immunosuppressive niche. Using a mouse model of carcinogen-induced fibrosarcomas, we
have examined how Treg depletion impacts on tumour growth. Results of the study show that tumour re-
gression after Treg-depletion is highly variable and observed in only a proportion of animals. Comparing the
genotype and phenotype of tumours recovered from responder and non-responder mice reveals several key
features of the tumour microenvironment that distinguish the two groups. These include the type of blood
vessels present, the composition of the extracellular matrix and the number of tumour infiltrating lympho-
cytes. The reciprocal influences of these features will be discussed as well as the potential for manipulating
the tumour microenvironment in order to maximise the success of T cell-based immunotherapies.

14. Combination immunotherapies: aiming at the tumour microenvironment

Gareth Thomas

University of Southampton, UK

Using next generation sequencing and bioinformatic analyses combined with multiplexed immunochem-
istry, we have characterised molecular features of the tumour microenvironment that are associated with
effective/ineffective anti-cancer immune responses, characterising prognostic/predictive lymphocyte sig-
natures and identifying immune evasion mechanisms that are common across different types of cancer. In
vivo preclinical testing confirms that specific evasion mechanisms can be targeted to improve response to
standard immunotherapies, and suggests strategies for combination immunotherapies based on immune
classification of tumours.