The immune system is constantly defending the body against invading bacteria, viruses and parasites, but also against abnormal cells like cancer cells. Immune cells recognise and destroy cancer cells, however, sometimes cancer cells evade immune surveillance.
Cancer cells can change the expression of certain markers on their cell surface which makes them unrecognisable to killer immune cells. They can also establish an immunosuppressive tumour environment. The recruitment of monocyte-derived suppressor cells and regulatory T cells (Tregs) reduces immune activation and is a major cause of resistance to chemotherapy. This gives cancer cells a growth advantage, allowing them to develop largely unchecked.
Check-point inhibitors are antibodies (targeting PD-1, PDL-1 and CTLA-4) that have been developed to “take the brake off T cells” and thereby re-instate T cell-mediated cell killing. Such immunotherapies are currently in clinical trials and have successfully treated patients with skin melanoma.
Oncolytic virotherapies are an emerging and exciting area of immunotherapy development. Oncolytic viruses are engineered to selectively replicate in and destroy cancer cells while sparing healthy cells. They can also be armed with anti-PD-1, anti-CTLA-4 antibodies or GM-CSF to activate the immune system and a number of these engineered oncolytic viruses are in clinical trials. The combination of oncolytic cell killing and immune activation has the potential to wage war on cancer. The major limitation to successful immunotherapy at present is resistance to chemotherapy.
A recent paper published in Cancer Cell by a group in the US (Hou et al., 2016) describe how they developed an oncolytic vaccinia virus that sensitises previously resistant tumour models to oncolytic vaccinia virus and anti-PD-1 immunotherapy. Syngeneic tumours (tumour cells derived from the same species of origin) were implanted in immunocompetent mice. Once the tumour reached a particular size, the mice were treated with a single injection of the oncolytic vaccinia virus (WR.TK-) into the tumour. Hou et al., 2016 found no correlation between resistant or sensitive tumour models with tumour cell death, viral replication or overall survival in mice. They hypothesised that factors other than oncolytic virus must be influencing overall survival. After virus therapy, sensitive tumour models demonstrated increased virus clearance in comparison to resistant tumour models, indicating activation of the immune system. Sensitive tumour models showed low baseline levels of monocyte-derived suppressor cells whereas the resistant counterparts showed high baseline levels indicating an immunosuppressive phenotype.
The COX-2-PGE2 signalling pathway is reported as a mediator of monocyte-derived suppressor cell recruitment to the tumour. HPGD (15-hydroxyprostaglandin dehydrogenase) is an inactivating enzyme of PGE2. In an attempt to overcome the high monocyte-derived suppressor cell levels in a resistant tumour model and to break the immunosuppressive cycle, they developed an oncolytic vaccinia virus over-expressing the HPGD transgene (WR.TK-HPGD+) to inhibit monocyte-derived suppressor cells.
Image from Hou et al., 2016.
Using mouse models of tumour resistance and sensitivity, the group demonstrated enhanced oncolytic activity in the sensitive models with the most therapeutic benefit observed in a resistant tumour model. They state that oncolytic infection alone caused immune activation but HPGD was required to prevent premature immune shutdown and enable establishment of adaptive immunity.
Furthermore, mice harbouring the same tumour on both flanks but injected with WR.TK- in one flank and WR.TK-HPGD+ on the other, showed significant trafficking of cytokine induced killer cells (CIK) to the WR.TK-HPGD+-infected tumour indicating significant immune activation in response to WR.TK-HPGD+. Interestingly, WR.TK-HPGD+ treatment sensitised a previously resistant tumour to anti-PD-1 immunotherapy. WR.TK-HPGD+ treatment in combination with anti-PD-1 resulted in increased therapeutic benefit, even in late established tumours. This was not observed with WR.TK- and anti-PD-1 therapy alone.
In conclusion, WR.TK-HPGD+ induced oncolytic cell death and altered the immune cell repertoire within the tumour, sensitising previously resistant tumours to oncolytic virus and other immunotherapies. This has huge potential for developing immunotherapies and treating human cancers in the clinic.
Hou, W., Sampath, P., et al. (2016). Oncolytic Virus-Mediated Targeting of PGE2 in the Tumor Alters the Immune Status and Sensitizes Established and Resistant Tumors to Immunotherapy. Cancer Cell. 30: 108-119.