Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice.

Oncogene 2020 Mar

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Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis. Here, we bypassed the embryonic lethality of dually PARP-1/PARP-2-deficient mice by using a PARP-1-deficient mouse with a Cd4-promoter-driven deletion of PARP-2 in T cells to investigate the understudied role of these PARPs in the modulation of T cell responses against AT-3-induced breast tumors. We found that dual PARP-1/PARP-2-deficiency in T cells promotes tumor growth while single deficiency of each protein limited tumor progression. Analysis of tumor-infiltrating cells in dual 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. Our findings pinpoint opposite effects of single and dual PARP-1 and PARP-2-deficiency in modulating the antitumor response with an impact on tumor progression, and will have implications for the development of more selective PARP-centered therapies.

Citation

Lucia Moreno-Lama, Miguel A Galindo-Campos, Carlos Martínez, Laura Comerma, Ivonne Vazquez, María Vernet-Tomas, Coral Ampurdanés, Nura Lutfi, Juan Martin-Caballero, Françoise Dantzer, Miguel Quintela-Fandino, Syed O Ali, Jaime Jimeno, José Yélamos. Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice. Oncogene. 2020 Mar;39(13):2835-2843