# Radiotherapy and Immunotherapy--A Future Partnership towards a New Standard
## 3 Radiotherapy and Immunotherapy: Abscopal and \"In Situ\" Vaccination Effect
report a case of the abscopal effect associated with ICI therapy and radiotherapy in non-small cell lung carcinoma (NSCLC). In this case, the abscopal effect was associated with the reactivation of the immune response to pembrolizumab after the cessation of the synergistic remote effect of immunotherapy and radiotherapy. Thus, the abscopal and the \"in situ\" vaccination effects induced by the association of immunotherapy with radiotherapy were successively established. The authors mention the need for detailed evaluation in clinical trials of this synergistic association of radiotherapy with PD-L1 inhibitors to be able to understand all the mechanisms involved, the identification of some biomarkers being one of the priorities in order to increase the percentage of \"responders\" [9; 20]. Preclinical data mention the detrimental effect on the abscopal effect of growth factor-\(\beta\) (TGF-\(\beta\)) in the TME by converting cytotoxic T lymphocytes (CTLs) into exhausted phenotypes. The absence of the thymus in mice was also associated with the lack of effect, demonstrating-thus the involvement of the innate immune host status and also the role of T lymphocytes in the immunotherapy-radiotherapy synergy. Exhaustion is considered to be a state of T lymphocytes associated with a reduction in the production of active cytokines, low cytotoxic activity, and an upregulation of inhibitory receptors [9; 31; 32; 33]. Due to the lymph opening effect, chemotherapy should theoretically have an immunosuppressive effect, detrimental to the tumor response to ICI therapy. However, depending on the cytotoxic agent, dose, regimen, and therapeutic sequence, chemotherapy can induce \"immunogenic cell death\" (ICD) by releasing tumor antigens that will stimulate an immune response sensitizing the surviving cells to the cell-killing mechanisms of the immune system. Apoptosis induced by chemotherapy, but also by endoplasmic reticulum stress of tumor cells, triggers signaling mechanisms that affect anti-tumor antigen-specific T cells and thus induce an \"in situ vaccination\" effect. At the same time, chemotherapy can relatively avoid the destruction of CD8+ and CD4+ T cells and of NK cells, but it contributes to the depletion of stromal components and MDSC, through this TME modulation effect, increasing the tumor response to immunotherapy [34; 35; 36; 37]. Radiotherapy and the ICD mechanism could decide the \"repositioning\" of chemotherapy in order to obtain a maximal immune-mediated antitumoral effect. In the case of carboplatin and paclitaxel, there is evidence of ICD potentiation through synergistic use. 5-fluorouracil and gemcitabine have a dual effect and for this reason, their association with concurrent irradiation is controversial. The positive effect of eliminating MDSCs and enhancing CD8 T cell-dependent immune responses can be counteracted by caspase-1 activation in MDSCs that promotes tumor growth [38]. Six mechanisms of ICD induced by irradiation are mentioned by [PERSON] et al., mitotic catastrophe, mitotic death, necrosis, senescence, necroptosis, and ferprotosis, explaining the heterogeneity of the immune response mediated by irradiation but also the multitude of factors involved in the synergistic effect [39]. The expression of DAMPs, HMGB, and Hsp70 are the molecules released after the lesions induced by spot irradiation that can be detected and can trigger the activation of innate immune response. Even if the results are contradictory, these molecules are currently being evaluated as possible biomarkers of ICD induced by irradiation [40]. Calreticulin a is among the most frequently evaluated DAMPs in relation to the response to radiotherapy. If in non-small cell lung carcinoma (NSCLC) patients treated with radiotherapy, calreticulin expression was identified as prognostic, in the case of esophageal cancer treated with chemoradiotherapy, calreticulin expression was not superior in the group treated with neoadjuvant treatment [40; 41].