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

Oncogene volume 39, pages 2835–2843 (2020)Cite this article

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Abstract

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.

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Fig. 1: Host-mice with deficiencies of PARP-1 and/or PARP-2 display differential changes in the growth of tumors harboring both PARP-1 and PARP-2 proteins.
Fig. 2: Analysis of spleen cells from mice hosting AT-3-induced tumors.
Fig. 3: T cell response to AT-3-induced breast tumors is modulated by PARP-1 and PARP-2 proteins.
Fig. 4: Dual PARP-1 and PARP-2 deficiency impacts on the expression of genes involved in cell migration and activation in tumor-infiltrating T cells.

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Acknowledgements

We thank Dr. Abrams Scott for giving us the AT-3 cell line, Mary Hensen for assistance with the AT-3 cell line, Gemma Torres-Sotodosos and Laura Regué for technical assistance, and Xavi Duran for statistical assistance. The Yélamos’s lab is funded by the Spanish Ministerio de Economía, Industria y Competitividad (grant SAF2017-83565-R) and The Fundación Científica de la Asociación Española Contra el Cáncer (AECC). The Dantzer’s lab is supported by LABEX ANR-10-LABX-0034_Medalis, Strasbourg University, CNRS.

Author information

Authors and Affiliations

  1. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

    Lucia Moreno-Lama, Miguel A. Galindo-Campos, Coral Ampurdanés, Nura Lutfi & José Yélamos

  2. Experimental Pathology Unit, IMIB-LAIB-Arrixaca, Murcia, Spain

    Carlos Martínez

  3. Department of Pathology, Hospital del Mar, Barcelona, Spain

    Laura Comerma, Ivonne Vazquez & José Yélamos

  4. Department of Obstetrics and Gynecology, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

    María Vernet-Tomas

  5. Barcelona Biomedical Research Park (PRBB), Barcelona, Spain

    Juan Martin-Caballero

  6. Biotechnology and Cell Signaling, UMR7242-CNRS, Laboratory of Excellence Medalis, ESBS, Illkirch, France

    Françoise Dantzer

  7. Breast Cancer Clinical Research Unit, CNIO, Madrid, Spain

    Miguel Quintela-Fandino

  8. Oxford University Hospitals, NHS, Oxford, UK

    Syed O. Ali

  9. Department of General Surgery, Breast Unit, Hospital Universitario Marqués de Valdecilla, Santander, Spain

    Jaime Jimeno

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  1. Lucia Moreno-Lama
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Contributions

LM-L carried out most of the experiments presented in the paper. JM-C, MG-C, and NL contributed to in vivo experiments. CM, LC, and IV carried out pathology studies. CA provided technical assistance. FD and MQ-F provided reagents. MV and JJ contributed to planned and designed experiments. SOA contributed to discussions and edited the paper. JY planned and designed experiments, performed experiments, and wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to José Yélamos.

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Moreno-Lama, L., Galindo-Campos, M.A., Martínez, C. et al. Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice. Oncogene 39, 2835–2843 (2020). https://doi.org/10.1038/s41388-020-1175-x

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