# Radiotherapy and Immunotherapy--A Future Partnership towards a New Standard
## 3 Radiotherapy and Immunotherapy: Abscopal and \"In Situ\" Vaccination Effect
[PERSON] et al. mention a possible detrimental antitumor effect when administering a standard fractionation regimen that can induce lymphopenia as in the case of head and neck cancers, but hypofractionated irradiation regimens seem to have an augmentation effect of antitumor immunity. Comparing the hypofractionated regimen 8 Gy \(\times\) 2 with the standard fractionation regimen 2 Gy \(\times\) 10, the study evaluated the immune correlations, the antitumor effect on the primary tumor, and the possibility of inducing the Abscopal effect. The activation and maintenance of peripheral and tumoral CD8+ T lymphocyte level, but also the reduction of peripheral and tumoral accumulation of MDSC was superior for the hypofractionated regimen. In addition, the hypofractionated regimen enhanced the expression of MHC class I and PD-L1 sensitivity to IFN using the 8 Gy \(\times\) 2 regimen, but the Treg level was not influenced by any of the irradiation regimens. IFN responses of CD8+ T lymphocytes in draining lymph nodes were also improved by the 8 Gy \(\times\) 2 regimen. Worth mentioning is the effect of limiting the responses of CD8+ T lymphocytes when the 2 Gy \(\times\) 10 regimen is used. The study demonstrates the ability of hypofractionated irradiation to maintain the antitumor immune response, and in the case of the association of anti-PD-1 therapy, hypofractionation, but not the standard irradiation regimen, can generate the reversal of adaptive immune resistance and the augmentation of the response to local and abscopal ICI dependent on CD8+ T lymphocytes. The results could be the basis for the design of new stages that exploit the synergistic potential of immunotherapy-- radiotherapy association [25]. The role of lymph nodes in mediating the abscopal antitumor response mediated by the association of radiotherapy with anti-PD-1 immunotherapy was investigated with the help of a modified subcutaneous B16F10 flank tumor model that allows the dynamic monitoring of tumor-specific T cells. Using irradiation of the primary tumor or of the tumor and lymph nodes the study evaluated both the response to treatment and the dynamics of tumor-specific T that infiltrate the primary tumor and lymph nodes. The authors also identify stem-like CD8+ T cells that populate the lymph nodes, which may infiltrate the primary tumor, much poorer in tumor-specific T. The effect of irradiation on this category of cells is still less known [26]. In most of the cases, the abscopal effect is induced by stereotactic body radiation therapy (SBRT), with lower doses \(\leq\)3 Gy per fraction up to a total dose \(\leq\)30 Gy not being considered immune stimulatory [1; 17; 27; 28]. The preclinical study by [PERSON] and collaborators demonstrated that four daily fractions of 3.2 Gy reduced the number of CD8+ T cells and APC lymphocytes in lung tumors, thus identifying potential risk to reduce the immune response associated with radiation therapy. For this reason, a new target volume for radiotherapy theory proposed the avoiding of the tumor-draining lymph nodes (TDLN) in order to reduce the destruction of CD8+ cells. The TDLN was of particular attention in the case of the use of CTLA-4 inhibitors, being considered an anatomical structure involved in the priming of T lymphocytes. Recent studies have also demonstrated the involvement of proliferating stem cell-like and progenitor-exhausted T cells in the TDLN in the response to therapy with PD inhibitors -1 [28; 29]. Analyzing 24 cases aged between 24 and 74 reported in 15 scientific papers, [PERSON] et al. identified median total doses between 18-58 Gy. Using the linear quadratic (LQ) formalism, the biologically effective dose (BED) 10 for the median tumoricidal effect was 49.65 Gy. The effect was identified at different time intervals after irradiation, ranging from more than one month to 12 months. All patients received immunotherapy as a systemic treatment, but the therapeutic sequence differed from case to case [30]. [PERSON] et al.