Recent data support that combining radiation therapy (RT) with immune checkpoint inhibitors (ICI) is a promising approach in cancer patients . To date, programmed death ligand 1 (PD-L1) on tumor cells is the only predictive biomarker validated but, so far, available data do not definitively suggest that PD-L1 expression is required for biologic activity of RT-ICI combinations. RT upregulates PD-L1 in cancer cells as a part of a cancer pro-survival program supposed to provide an additional opportunity for the use of ICI . Notably, whether RT-induced PD-L1 might represent a predictive biomarker of response or might simply mirror an immunosuppressed microenvironment is poorly understood. Despite RT is able to boost the immune activation in some patients for whom additional immunotherapy is supposed to be beneficial, in other cases it activates systemic host responses that contribute to treatment resistance .The fact that many patients early acquire resistance indicate that many potential immune suppressors may lead to cancer cells immune-escape, thus abrogating the radiation-induced priming function. Characterizing the molecular pathways activated in those tumor cells able to survive to RT-induced immunogenic death is consequently expected to deepen our understanding of radiation-associated immune regulation . For this to be achieved, it is necessary to have a global vision of how the immune escape related pathways change during treatment, a condition that would require repeated biopsies clearly not feasible during treatment, strongly impairing the reliability of hypothetical biomarkers in prior to therapy tumor samples as predictive biomarker of response. However, this limit can be overcome by using liquid biopsy, through the accessible and repeatable isolation of circulating tumor cells (CTCs) into the bloodstream. Aim of this proposal is to investigate the effects of RT on the immune escape enabling properties of CTCs in patients treated with RT.
A growing number of studies shows that radiation therapy might boost the immune activation in some patients for whom additional immunotherapy is mostly needed , but also activate systemic host responses that contribute to tumor re-growth and subsequent treatment resistance. Many potential immune suppressors may lead to cancer cells immune-escape, abrogating the radiation-induced priming function. This proposal is expected to deepen our understanding of radiation-induced mechanisms of immune escape in cancer cells using liquid biopsy that represents an optimal tool to assess predictive biomarkers in post-treatment samples. The study of CTCs has elicited increasing interest for translational applications such as the early identification of treatment resistance. In the immuno-oncology era, the analysis of CTCs enabled to understand several mechanisms of immune escape, including the downregulation or loss of surface major histocompatibility class I (MHCI) expression , the acquisition of epithelial-mesenchymal transition (EMT) phenotype , the expression of PD-L1, the interaction with platelets, and the generation of clusters (8). To date, the effects of RT on the immune escape enabling properties of CTCs have never been investigated. Deciphering the link between radiation therapy and immune escape enabling features of CTCs would be important to provide a novel preclinical rationale to explore new inhibitors to boost immunotherapeutic responses.
References
1. Alfonso JCL, Papaxenopoulou LA, Mascheroni P, Meyer-Hermann M, Hatzikirou H On the Immunological Consequences of Conventionally Fractionated Radiotherapy.iScience. 2020 Feb 11;23(3):100897. doi: 10.1016/j.isci.2020.100897
2. Arina A, Gutiontov SI, Weichselbaum RR. Radiotherapy and immunotherapy for cancer: From "systemic" to "multi-site".Clin Cancer Res. 2020 Feb 11. pii: clincanres.2034.2019. doi: 10.1158/1078-0432.CCR-19-2034
3. De Guillebon E, Dardenne A, Saldmann A, Séguier S, Tran T, Paolini L, Lebbe C, Tartour E.Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination. Int J Cancer. 2020 Jan 30. doi: 10.1002/ijc.32889
4. Gong J, Le T , Massarelli E, Hendifar A , Tuli R .Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. .J immunotherapy cancer 6, 46 (2018). https://doi.org/10.1186/s40425-018-0361-7
5. Sundahl N, Duprez F, Ost P, De Neve E, Mareel M Effects of radiation on the metastatic process. Mol. Med, https://doi.org/10.1186/s10020-018-0015-8, 2018
6. Buder A, Tomuta C, Filipits M. The potential of liquid biopsies. Curr Opin Oncol. 2016;28(2):130-4.
7. Nicolazzo C , Raimondi C, Mancini ML et al. Monitoring PD-L1 Positive Circulating Tumor Cells in Non-Small Cell Lung Cancer Patients Treated With the PD-1 Inhibitor Nivolumab Sci Rep 2016 Aug 24;6:31726. doi: 10.1038/srep31726.
8. Leone K, Poggiana C, Zamarchi R.The Interplay between Circulating Tumor Cells and the Immune System: From Immune Escape to Cancer Immunotherapy. Diagnostics (Basel). 2018 Aug 30;8(3). pii: E59. doi: 10.3390/diagnostics8030059.