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Lymphodepletion before adoptive cell transfer (ACT)-based immunotherapies can enhance anti-tumor responses by augmenting innate immunity, by increasing access to homeostatic cytokines, and by depressing the numbers of regulatory T cells and myeloid-derived suppressor cells. Although it is clear that high-dose total body irradiation given together with hematopoietic stem cell (HSC) transplantation effectively enhances ACT, the relationship between the intensity of lymphodepletion and tumor treatment efficacy has not been systematically studied. Using the pmel-1 mouse model of self/tumor-reactive CD8+ T cells, we observed a strong correlation between the intensity of the conditioning regimen and the efficacy of ACT-based treatments using linear regression analysis. This was the case for preparative total body irradiation administered either as a single dose (R2=0.97, P<0.001) or in fractionated doses (R2=0.94, P<0.001). Increased amounts of preparative total body irradiation were directly correlated with progressively more favorable ratios of transferred tumor-reactive CD8+ T cells toward endogenous cells with the potential for inhibitory activity including: CD4+ cells (potentially T regulatory cells); Gr1+ cells (which are capable of functioning as myeloid-derived suppressor cells); and endogenous CD8+ and natural killer 1.1+ cells (that can act as “sinks” for homeostatic cytokines in the postablative setting). With increasing ablation, we also observed elevated lipopolysaccharide levels in the sera and heightened levels of systemic inflammatory cytokines. Thus, increased intensity lymphodepletion triggers enhanced tumor treatment efficacy and the benefits of high-dose total body irradiation must be titrated against its risks.