Translational Therapeutics

Sourcing the immune system to induce immunogenic cell death in Kras-colorectal cancer cells

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Abstract

Background

Current approaches aimed at inducing immunogenic cell death (ICD) to incite an immune response against cancer neoantigens are based on the use of chemotherapeutics and other agents. Results are hampered by issues of efficacy, combinatorial approaches, dosing and toxicity. Here, we adopted a strategy based on the use of an immunomolecule that overcomes pharmachemical limitations.

Methods

Cytofluorometry, electron microscopy, RT-PCR, western blotting, apotome immunofluorescence, MLR and xenografts.

Results

We report that an ICD process can be activated without the use of pharmacological compounds. We show that in Kras-mut/TP53-mut colorectal cancer cells the 15 kDa βGBP cytokine, a T cell effector with onco-suppressor properties and a potential role in cancer immunosurveillance, induces key canonical events required for ICD induction. We document ER stress, autophagy that extends from cancer cells to the corresponding xenograft tumours, CRT cell surface shifting, ATP release and evidence of dendritic cell activation, a process required for priming cytotoxic T cells into a specific anticancer immunogenic response.

Conclusions

Our findings provide experimental evidence for a rationale to explore a strategy based on the use of an immunomolecule that as a single agent couples oncosuppression with the activation of procedures necessary for the induction of long term response to cancer.

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Acknowledgements

L. Mallucci thanks Professor Tony Ng for interest and support and for reviewing the manuscript and Professor Richard Trembath for support. L. Mallucci and V. Wells thanks Dr Juergen Moll for comments on the manuscript. R. Mariani-Costantini and L.V. Lotti thank Professor Fabio Pulcinelli for the gift of ATP reagents and Mr Sandro Valia for assistance with art work.

Author information

L.M. conceived research, led research and prepared manuscript with contributions from V.W. and R.M.-C.; L.M., R.M.-C., M.C., L.V.L., I.B., M.Ct. and V.W. designed experiments; M.C., L.V.L., M.G., M.Ct., L.D.R., I.B., S.V., F.V., D.D. and V.W. performed research; L.M., R.M.-C., M.C., L.V.L., L.D.R., V.W., I.B. and M.Ct. analysed data; R.M.-C. and F.V. carried out in vivo studies, R.M.-C. coordinated work.

Correspondence to Livio Mallucci.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

We confirm that that the donation of blood cells by human subjects complies with the Declaration of Helsinki. Donors gave their informed consent. Approval was given by the Comitato Etico Policlinico Umberto Primo Roma.

Funding

The work was supported by internal funding from King’s College London, Universita’ di Roma La Sapienza, and the G.d’Annunzio University Chieti.

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All authors consent to publication of this paper.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Cirone, M., Lotti, L.V., Granato, M. et al. Sourcing the immune system to induce immunogenic cell death in Kras-colorectal cancer cells. Br J Cancer 121, 768–775 (2019) doi:10.1038/s41416-019-0561-z

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