# Radiotherapy and Immunotherapy--A Future Partnership towards a New Standard
## 5 Conclusions  
Two new effects will govern the future of the immunotherapy-radiotherapy association: the local \"in situ\" vaccination effect and the systemic remote \"abscopal\" response. Even if irradiation by stereotactic body irradiation (SBRT) or stereotactic radiosurgery (SRT) seems to be more effective in generating the synergistic effect, the PACIFIC trial demonstrates the role of conventional irradiation in combination with chemotherapy in modulat  
\begin{table}
\begin{tabular}{c c c} \hline
**Target Organ/Organ at** & **Radiation Dose/Regimen** & **Toxicity Reported** \\
**Risk (OAR)** & & \\ \hline Whole brain & 24–25 Gy & Long term RIL [71] \\ \hline \multirow{2}{*}{Breast} & Effective dose to the circulating immune cells & \multirow{2}{*}{50\% of grade 1, grade 2, and grade 3 RIL [72]} \\  & (EDIC) of 1.2, 2.1 and 3.7 Gy, respectively & \\ \hline \multirow{2}{*}{Esophagus} & Larger planning target volume (PTV), higher & Lymphocyte nadir after 4-6 weeks of \\  & heart and body dose, higher EDIC & radiotherapy [73] \\ \hline \multirow{2}{*}{Brain (glioma), lung, pancreas} & Field size, dose per fraction, and fraction number & Increased risk of RIL [74] \\  & SBRT, Proton therapy & Reduction of RIL risk [74] \\ \hline \multirow{2}{*}{Spleen} & Volumes receiving at least 5 Gy (V15) and & Nadir lymphocyte count [75] \\  & maximum dose (Dmax) & 1\% decrease in absolute lymphocyte count at \\  & an increase of 1 Gy in mean splenic dose & nadir [75] \\ \hline \multirow{2}{*}{Esophagus} & EDIC \textless{} 2, 2 to 4, and \textgreater{}4 Gy, respectively & 2-year OS rates were 66.7\%, 42.7\%, and 16.7\% [76] \\ \hline \end{tabular}
\end{table}
Table 2: Dosimetric predictors of RIL.  
ing the host's immune response. Thus, the radiotherapy-chemotherapy-immunotherapy triad may become the future standard in locally advanced diseases. The different mechanisms of producing immune-mediated cell death and the indirect role of augmenting the immune effect induced by radiotherapy make the old theories related to the therapeutic sequence, fractionation, doses, and target volumes as well as the protection of healthy tissues to be reevaluated. The new concept has as a substrate the possibilities of modulating the immunosuppressive and activating factors of the immune system so as to amplify the anti-tumor immune-mediated tumoricidal response by suppressing the immunosuppressive factors and activating the immune effectors in the TME. The selection of therapeutic targets chosen for the combination of immunotherapy and associated radiotherapy can be conducted based on the classification of tumors in the three immune phenotypes that characterize \"cold\" and \"hot\" tumors from the point of view of the response to therapy. The complexity of the synergistic mechanisms that could enhance but also suppress the anti-tumor immune response makes it necessary to translate the preclinical data for each histological subtype of the tumor and combination regimen of immunotherapy with radiotherapy and chemotherapy, as it is obvious that there is no universal solution. Omitting elective irradiation of draining lymph nodes is one of the most promising strategies, but must be approached with caution in order not to compromise loco-regional control.  
Conceptualization, C.C.M., R.I.I. and D.T.I.; methodology, C.C.M.; validation, R.I.I. and D.T.I.; writing--original draft preparation, C.C.M.; writing--review and editing, R.I.I. and D.T.I.; supervision, R.I.I. and D.T.I. All authors have read and agreed to the published version of the manuscript.  
This research received no external funding.  
Not applicable.  
The authors declare no conflict of interest.