# Radiotherapy and Immunotherapy--A Future Partnership towards a New Standard
## 3 Radiotherapy and Immunotherapy: Abscopal and \"In Situ\" Vaccination Effect  
The importance of the host's immune response in relation to the benefit of radiotherapy was highlighted more than 60 years later by [PERSON] and colleagues, finding the need for a 50% escalation of the irradiation dose in order to obtain the same tumoricidal response in the cases of immune-compromised mice. The concept of \"in situ\" vaccination represents an approach in which the antitumor vaccine is generated in vivo without being prepared and processed outside the host. The advantage is conferred by the exploitation of tumor-associated antigens (TAA) available at the site of the tumor without the need for their identification and isolation. The much higher expression of TAA in tumor tissue than in normal tissue opens perspectives for the use of this method as an anti-cancer strategy. Through the processing of TAA by antigen-presenting cells (APC), the antitumor response mediated by T lymphocytes is activated [18]. Radiotherapy has the potential to stimulate the release of TAA and the presentation of antigens to the dendritic cell (DC) with an immune stimulatory effect. Thus, radiotherapy acts locally at the level of the tumor like \"in situ\" vaccines. DC are APCs with a role not only in inducing an anti-tumor immune response but also in maintaining T cell tolerance to self-antigens. Additionally, the induction of a long-lasting antitumor response depends on the ability of the radiotherapy to maximize the absorption of the APC antigen. In this way, activated T cells will not need co-stimulatory signals to activate tumor destruction mechanisms. The release of the destroyed DNA fragments also results in the release of new tumor antigens that generate an immune response via the major histocompatibility complex (MHC). The release of natural killer (NK) cells and the alteration of the rigidity of the extracellular matrix are other phenomena involved in the potentiation of the antitumor immune response. However, alteration of the extracellular matrix is generally reported at high doses per fraction, possibly more associated with SBRT. Damage to the vascular endothelium by inducing apoptosis and limiting blood flow by limiting the recruitment of cytotoxic T cells is also reported at higher doses per fraction irradiation. However, at typical doses of conventional irradiation, there is an additional generation of adhesion molecules that favor the trafficking of T lymphocytes and the potentiation of the immune response. However, it should be noted that radiotherapy also has effects on some components with an immunosuppressive role, among which we mention regulatory T cells (T-regs), mesenchymal-derived suppressor cells (MDSCs), and M2 macrophages [19; 20]. The abscopal effect produced by irradiation refers to a clinical phenomenon induced by localized irradiation, a systemic response being produced in a metastatic site located in a non-irradiated region. In the absence of one or two ICIs systemic treatment, the abscopal phenomenon is considered rare. For the first time, the abscopal effect is reported by [PERSON] et al. in 1953 [21; 22]. [PERSON] et al. mention the case of a 70-year-old male patient, who was diagnosed with a left cervical tumor formation and an abdominal tumor mass, the diagnosis is considered an unknown primary squamous cell carcinoma. In this case, irradiation with a total dose of 60 Gy in 30 daily fractions on the left cervical mass induced a favorable response in the case of the abdominal tumor [23]. The systematic literature review proposed by [PERSON] et al. identified 46 cases over a period of 45 years, in all cases no systemic treatment was associated with irradiation [24]. The preclinical data highlights an essential aspect of combining radiotherapy with immunotherapy: the different effects of dose/fractionation regimes and irradiated volumes on the synergistic potential of radiotherapy-immunotherapy, the balance being fragile between immunosuppression and potentiation of the antitumor immune effect [19; 23].