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Abstract
Background Therapies which augment anti-cancer immune responses, such as immune checkpoint inhibitors (ICIs), have revolutionised cancer treatment in recent years. Despite inducing durable responses across different cancer types, not all patients respond to treatment. To fully exploit the potential of immuno-oncology (IO) agents, combinations with other therapeutic modalities such as radiotherapy or DNA damage response (DDR) agents are being investigated in preclinical models and clinical trials. Characterising the effects of IO therapies in combination with radiotherapy and DDR agents on the tumour immune microenvironment (TIME) is therefore valuable to inform drug discovery research.
Methods The response of syngeneic cancer models to ICIs, fractionated radiotherapy and DDR agents was evaluated by measuring tumour growth with callipers three times per week. Mice receiving IR therapy were administered targeted X-rays using a Xstrahl CIX3 cabinet irradiator, and animals were shielded using lead panels with only the tumour exposed for localised treatment. Changes to the TIME following treatment with these therapies was evaluated using multi-colour flow cytometry and Jess automated western blot.
Results Treatment with ICIs led to a mixed response, with tumour regressions obtained in a fraction of the animals treated. The combination of ICIs with fractionated radiotherapy or DDR agents significantly increased the therapeutic efficacy. Characterising the TIME following treatment with ICIs, fractionated radiotherapy or DDR agents revealed that these therapies modulate the intratumoural immune infiltrate. Notably, a significant decrease in the frequency of tumour associated macrophages and increase in CD8+ cytotoxic T cells was observed in tumours treated with the combination of anti-PD-1 and fractionated IR.
Conclusions We have characterised and established efficacious dosing regimens for ICIs, fractionated radiotherapy and DDR agents and evaluated changes to the TIME in syngeneic mouse cancer models. These data demonstrate the value of these models for IO drug discovery research.
Ethics Approval All animal work was carried out under UK Home Office legislation, ASPA 1986, Agenda resource management (Alderley Park) AWERB
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