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Poster Display session

360 - Dissecting the antitumor immune response upon PARP inhibition in homologous recombination repair (HRR)-deficient tumors


14 Dec 2018


Poster Display session


Benedetta Pellegrino


Annals of Oncology (2018) 29 (suppl_10): x1-x10. 10.1093/annonc/mdy493


B. Pellegrino1, A. Llop-Guevara2, C. Cruz3, M. Castroviejo4, A. Cedro-Tanda5, R. Fasani6, P.G. Nuciforo7, A. Gros8, J. Balmaña9, M.J. O'Connor10, V. Serra Elizalde2

Author affiliations

  • 1 Oncology, AOU di Parma, 43126 - Parma/IT
  • 2 Experimental Therapeutics Group, Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 3 Medical Oncology, Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 4 Experimental Therapeutics Group, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 5 Instituto Nacional De Medicina Genómica, Universidad Nacional Autónoma de México, 14610 - Ciudad de Mexico/MX
  • 6 Pathology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 7 Molecular Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 8 Tumor Immunology And Immunotherapy, Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 9 Medical Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 10 Oncology, AstraZeneca R&D UK, CB10 1XL - Cambridge/GB


Abstract 360


HRR-deficient tumors are sensitive to PARP inhibitors (PARPi) and exhibit high levels of cytosolic DNA that can result in the activation of innate immune signaling as well as upregulation of PD-L1, which has the potential to suppress the immune response. We aimed to study if PARPi-induced PD-L1 upregulation limits the antitumor activity of PARPi by inhibiting the antitumor immune response, and if this is counteracted by anti-PD-L1 treatment.


30 Patient-Derived breast (BrC) and ovarian cancer (OvC) Xenografts (PDXs) were implanted in NMRI mice and tested for the PARPi olaparib sensitivity (5 BRCA2-, 23 BRCA1-, 2 PALB2-mutated). Their response was categorized according to the modified RECIST criteria as Complete (CR), Partial (PR) Response, Stable (SD) or Progressive (PD) Disease. RNASeq analyses were performed in PDX samples. We quantified PD-L1, CD45 (leucocyte marker), CD56 (NK cell marker) and CD11b (myeloid cell marker) positive cells by IHC in PDXs and clinical samples. Patient-derived tumor cell models (PDCs) were established (n = 17).


7 PDXs were classified as responders (CR/PR) and 23 as non-responders (SD/PD) to PARPi. At baseline, non-responder tumors expressed several pro-inflammatory genes (TNF, IL1A, IL33 and CXCL11) and exhibited a negative regulation of genes related to leukocyte proliferation by RNASeq compared to responders. In PARPi-sensitive tumors, olaparib treatment significantly increased infiltration of non-NK/non-myeloid-CD45+ immune cells, while in non-responders there was a marked increase in PD-L1 expression. Ex vivo cultures and PDXs recapitulated the patient’s PARPi response and PD-L1 expression, and are being prospectively used to investigate whether the PARPi-induced PD-L1 activation sensitizes to anti-PD-L1 therapy by enhancing the antitumor immune response.


In experimental models, olaparib elicits an antitumor immune response in PARPi-sensitive tumors that is not observed in PARPi-resistant tumors, which upregulate PD-L1. In these cases, the combination with anti-PDL1 therapy could enhance PARPi response.

Editorial acknowledgement

This Research Project was supported by ESMO with the aid of a grant from Roche. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche.

Clinical trial identification

Legal entity responsible for the study

Vall d\'Hebron Institute of Oncology.




J. Balmaña: Advisory board member: Clovis, Tesaro, Medivation; Speaker bureau honoraria: AstraZeneca. M.J. O\'Connor: Employee of AstraZeneca. V. Serra Elizalde: Non-commercial research agreement: AstraZeneca. All other authors have declared no conflicts of interest.

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