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Proffered Paper – Translational research

1691 - PARP inhibition increases immune infiltration in homologous recombination repair (HRR)-deficient tumors


28 Sep 2019


Proffered Paper – Translational research


Tumour Site

Breast Cancer


Benedetta Pellegrino


Annals of Oncology (2019) 30 (suppl_5): v760-v796. 10.1093/annonc/mdz268


B. Pellegrino1, A. Llop-Guevara2, F. Pedretti2, C. Cruz2, M. Castroviejo3, A. Cedro-Tanda4, R. Fasani5, F. Mateo6, A. Musolino7, M.A. Pujana6, P.G. Nuciforo8, A. Gros9, J. Balmana10, M.J. O'Connor11, V. Serra Elizalde12

Author affiliations

  • 1 Oncology, Azienda Ospedaliera Universitaria di Parma, 43125 - Parma/IT
  • 2 Experimental Therapeutics Group, Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 3 Experimental Therapeutics Group, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 4 Genomic, National Institute of Genomic Medicine, 14610 - Ciudad de Mexico/MX
  • 5 Molecular Oncology Group, Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 6 Breast Cancer Research Group, Institut Català d'Oncologia, 08908 - Hospitalet de Llobregat/ES
  • 7 Breast Unit, Azienda Ospedaliera di Parma, 43126 - Parma/IT
  • 8 Molecular Oncology, Vall d'Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 9 Tumor Immunology And Immunotherapy, Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 10 Hereditary Cancer Genetics Group, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 11 Oncology, AstraZeneca R&D UK, CB10 1XL - Cambridge/GB
  • 12 Experimental Therapeutics Group Dept., Vall d'Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES


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Abstract 1691


HRR-deficient tumors are sensitive to PARP inhibitors (PARPi) and exhibit high levels of cytosolic DNA that can result in the activation of the STING pathway as well as upregulation of PD-L1. We aimed to address such controversy by studying whether PARPi-induces PD-L1 upregulation and limits PARPi efficacy, and if this is counteracted by anti-PD-L1 treatment.


25 Patient-Derived breast cancer (BrC) (19 BRCA1/2-mutated and 2 PALB2-mutated) and 3 ovarian cancer (OvC) Xenoimplant (PDXs) models grown in NMRI-Foxn1nu/nu exclusively lacking T cells were generated, exome sequenced and tested for the PARPi olaparib antitumor response, which were categorized according to the modified RECIST criteria as Complete or Partial Response (CR/PR), Stable or Progressive Disease (SD/PD). We also used the Brca1f22 − 24 transgenic mouse model (Tg). We quantified cells expressing CD45 (leukocytes), CD56 (NK cells), CD11b (myeloid cells) and CD3 (T cells) by IHC in PDXs and Tg. We analyzed PD-L1 expression by IHC in PDXs and by flow cytometry in Tg.


BrC and OvC PDXs show distinct PARPi olaparib sensitivity (n = 5 CR, n = 3 PR, n = 3 SD and n = 17 PD) that fully correlates with the HRR-status, as measured by RAD51 foci. In PARPi-sensitive tumors (CR+PR), olaparib treatment significantly increases infiltration of stromal non-NK/non-myeloid-CD45+ immune cells. In contrast, in non-responders there is a recruitment of peritumoral non-NK/non-myeloid-CD45+ immune cells. PD-L1 is expressed in 40% PARPi non-responding models and it is not upregulated upon PARPi treatment (threshold 1%). Olaparib treatment in BRCA1-mutated Tg mice significantly increases infiltration of intratumoral CD3+ immune cells and stromal myeloid cells. PD-L1 in Tg tumor cells is maintained upon PARPi albeit it is expressed in intratumoral CD3+ cells.


In experimental models, olaparib elicits an antitumor immune response in PARPi-sensitive tumors. The expression of PD-L1 in tumors with poor responses to PARPi and in intratumoral lymphocytes suggests the combined use with anti-PD-L1 therapy. We are currently testing the combination of olaparib with anti-PDL1, and efficacy results will be presented at the meeting.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Vall d’Hebron Institute of Oncology.




A. Musolino: Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (self): Macrogenics; Travel / Accommodation / Expenses: Eisai. J. Balmana: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy: BMS; Advisory / Consultancy: Tesaro; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar. M.J. O’Connor: Full / Part-time employment: AstraZeneca. V. Serra Elizalde: Research grant / Funding (self): AstraZeneca. All other authors have declared no conflicts of interest.

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