TY - JOUR
T1 - The CD47/TSP-1 axis
T2 - a promising avenue for ovarian cancer treatment and biomarker research
AU - Moniot, Aurélie
AU - Schneider, Christophe
AU - Chardin, Laure
AU - Yaniz-Galende, Elisa
AU - Genestie, Catherine
AU - Etiennot, Marion
AU - Henry, Aubéri
AU - Drelon, Coralie
AU - Le Formal, Audrey
AU - Langlois, Benoit
AU - Venat, Laurence
AU - Louvet, Christophe
AU - Favier, Laure
AU - Lortholary, Alain
AU - Berton-Rigaud, Dominique
AU - Dohollou, Nadine
AU - Desauw, Christophe
AU - Fabbro, Michel
AU - Malaurie, Emmanuelle
AU - Dubot, Coraline
AU - Kurtz, Jean Emmanuel
AU - Bonichon Lamichhane, Nathalie
AU - Pujade-Lauraine, Éric
AU - Jeanne, Albin
AU - Leary, Alexandra
AU - Dedieu, Stéphane
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12/1
Y1 - 2024/12/1
N2 - Background: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis. Methods: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma. Results: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy. Conclusions: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.
AB - Background: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis. Methods: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma. Results: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy. Conclusions: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.
KW - CD47
KW - Neoadjuvant chemotherapy
KW - Ovarian cancer
KW - PARP
KW - TSP-1
UR - http://www.scopus.com/inward/record.url?scp=85201249488&partnerID=8YFLogxK
U2 - 10.1186/s12943-024-02073-0
DO - 10.1186/s12943-024-02073-0
M3 - Article
C2 - 39138571
AN - SCOPUS:85201249488
SN - 1476-4598
VL - 23
JO - Molecular Cancer
JF - Molecular Cancer
IS - 1
M1 - 166
ER -