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.
Vall d’Hebron Institute of Oncology.
AstraZeneca.
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.