CD47 expression in ovarian cancer: Dynamic correlation with lymphocyte and macrophage features as well as thrombospondin-1 (TSP-1) under neoadjuvant chemotherapy.
Authors: Leary Alexandra , Schneider Christophe , Chardin Laure , Yaniz-Galende Elisa , Genestie Catherine , Drelon Coralie , Moniot Aurélie , Venat-Bouvet Laurence , Louvet Christophe , Favier Laure , Lortholary Alain , Berton-Rigaud Dominique , Dohollou Nathalie , Desauw Christophe , Fabbro Michel , Malaurie Emmanuelle , Dubot Coraline , Kurtz Jean Emmanuel , Bonichon-Lamichhane Nathalie , Dedieu Stéphane 
Published: June 2023

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Background: To date, the results of immunotherapy strategies to treat ovarian cancer (OC) have been unfulfilling. A more comprehensive knowledge of the intricate immune tumor microenvironment (iTME) as well as the effects of chemotherapy on immune features may reveal novel immune targets. CD47 is overexpressed in OC and correlates with shorter survival and immune evasion via interaction with circulating ligands such as TSP-1. Little is known about how the CD47 receptor or its ligand TSP-1 changes under chemotherapy or their association with other features of iTME. In the randomized CHIVA trial, we therefore investigated CD47 expression in OC patients at diagnosis and after neoadjuvant chemotherapy (NACT) and assessed its relationship to other iTME features, including circulating level of thrombospondin-1 (TSP-1). Methods: Tumour samples were collected from 105 patients from the CHIVA trial, a GINECO-GINEGEPS study. CD47 expression was assessed by IHC in paired samples before and after NACT and scored by H-score: staining intensity (0, +1, +2, +3) x % cells positive (0-300). At baseline, we defined a CD47high (highest quartile, score above 240) and CD47low population (lowest quartile, score under 150). CD4+, CD8+, CD68+, CD163+, FoxP3+ cells were assessed by IF and scored as number of positive cells. The Pearson correlation coefficient (r) was used to determine the linear correlation between CD47 expression and other immune markers. Circulating TSP-1 was quantified by ELISA on paired plasma samples pre- and post-NACT. Results: While CD47high does not correlate with CD4 and CD8 expression at baseline, a correlation with CD8 (r=0.59, p=0.02) and a trend with CD4 (r=0.49, p=0.05) is observed after NACT. These linear correlations do not exist in the CD47low population. In addition, NACT induces a 2-fold decrease in FoxP3+ cells, but only within the CD47high group (p=0.028). Thus, both the CD4+/FoxP3+ (p=0.001) and CD8+/FoxP3+ (p=0.005) ratios were increased by 2-fold under NACT, exclusively in OC patients with CD47high expression. Interestingly, these correlations appear to be T-cell specific as no correlation exist when considering CD68 and CD163 before or after NACT, neither for CD47high nor CD47low. In parallel, we determined that the plasma level of TSP-1, a preferential CD47 agonist, was very high (>1500 ng/mL) in OC patients and decreased by about 2-fold after NACT. Interestingly, a pattern emerges in which the highest level of circulating TSP-1 is associated with the CD47lowpopulation. Conclusions: Our data suggest that OC patients with the highest CD47 expression profile at baseline have greatest lymphocyte influx post-NACT and may be most likely to benefit from post-operative immunotherapy. Whether blocking the immune-suppressive CD47:TSP1 interaction in this subset would provide an alternative strategy merits investigation. Clinical trial information: NCT01583322 .