Resumen de Understanding the immunomodulatory role of parp proteins in the response against tumors
Introduction and theoretical context: Poly(ADP-ribose)-polymerases (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARPs in the malignant cell itself, PARP inhibitors have emerged as new therapeutic approaches both in clinical trials and as already approved drugs. However, the complex interaction of multiple other cell types, particularly T cells, within the tumor microenvironment is determinant to either favor or limit tumorigenesis. PARP’s implication in cancer immunity is still poorly understood.
Aim and methodological approach: Bypassing the embryonic lethality of dually PARP-1/PARP-2-deficient mice, in the present work we investigate the understudied role of these PARPs in the modulation of T cell responses against AT-3-induced breast tumors, using a PARP-1-deficient mouse with a Cd4-promoter-driven deletion of PARP-2 in T cells.
Results: We report that dual PARP-1/PARP-2-deficiency in T cells promotes tumor growth while single deficiency of each protein limits tumor progression. Analysis of tumor-infiltrating cells in dually PARP-1/PARP-2-deficiency host-mice revealed a global change in immunological profile and impaired recruitment and activation of T cells. Conversely, single PARP-1 and PARP-2-deficiency tends to produce an environment with an active and partially upregulated immune response.
Conclusions: Our findings pinpoint opposite effects of single and dual PARP-1 and PARP-2-deficiency in modulating the anti-tumor response with a significant impact on tumor progression; thus highlighting the importance of developing more selective PARP-centered therapies.
