Abstract LB035: B7-H3 as a therapeutic target in prostate cancer

Abstract

Background: Advanced prostate cancer (PC) is invariably fatal and largely insensitive to established immune checkpoint inhibition (ICI). The immune checkpoint, PD-L1 (B7-H1; CD274), is infrequently overexpressed in PC; whilst other B7 family immunomodulatory glycoprotein, B7-H3 (CD276), is overexpressed in many PCs. B7-H3 targeted immunoconjugates are in clinical development. We therefore studied the longitudinal expression of B7-H3 in PC and its associations with advanced PC immunogenomics. Design: We analysed matching, same-patient, formalin-fixed paraffin-embedded (FFPE) metastatic castration resistant PC (mCRPC) (n=98), and treatment-naïve, castration-sensitive PC (CSPC) biopsies (n=43) from patients treated at The Royal Marsden Hospital (UK). Biopsies were analysed by: targeted next-generation sequencing (NGS) for deleterious DNA repair gene alterations; immunohistochemistry (IHC) for ATM, PTEN, B7-H3 and mismatch repair (MMR) proteins using validated antibodies; and multi-color immunofluorescence (IF) assays for T cell surface markers to determine the density of tumour infiltrating T lymphocyte (TIL) subsets. Wilcoxon signed-rank test and Mann-Whitney U test compared B7-H3 expression across matched and unmatched subsets, respectively. Spearman correlation determined associations between continuous variables. Results: Most CRPC and CSPC biopsies had both membranous B7-H3 (mB7-H3) expression (134/141, 95.0%) and cytoplasmic B7-H3 expression (137/141, 97.2%). Analysis of the 43 matched samples sets showed that there was no significant change in mB7-H3 expression as tumours progressed from CSPC to CRPC (median Histoscore [HS] [range]: 130 [5-300] for CSPC vs. 130 [5-290] for CRPC; p=0.6). There was significant interpatient and intratumor heterogeneity in mB7-H3 expression, but a subset of tumour biopsies had very high mB7-H3 expression (HS ≥200: 28/98 [28.6%] CRPC; 14/43 [32.6%] CSPC). mB7-H3 expression strongly associated with the presence of deleterious alterations of genes involved in homologous recombination (HR) repair (p<0.0001), including BRCA2 mutations and homozygous deletions (p=0.0003) as well as ATM loss (p=0.001). mB7-H3 expression did not associate with defective MMR. Interestingly, mB7-H3 expression inversely associated with the density of intra-tumor CD3+ TILs (median: 104.6 TILs/mm2 in B7-H3 low tumors (HS < median) vs. 39.2 TILs/mm2 in B7-H3 high tumours (HS ≥ median), p=0.004) but did not associate with stromal TIL density (p=0.4). Conclusion: mB7-H3 is highly expressed in advanced PC, with higher expression associating with BRCA2 and ATM loss of function alterations and low intratumor TILs. B7-H3 may be an actionable target for treating this disease subset. Citation Format: Christina Guo, Ines Figueiredo, Bora Gurel, Matues Crespo, Jan Rekowski, Suzanne Carreira, Antje Neeb, Adam Sharp, Maria D. Fenor de la Maza, Pasquale Rescigno, Khobe Chandran, Ana Ferreira, Ruth Riisnaes, Susana Miranda, Rita Pereira, Veronica Gil, George Seed, Claudia Bertan, Chloe Baker, Wei Yuan, Johann S. de Bono. B7-H3 as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB035.

The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer

“…Moreover, CD276 is highly expressed in advanced prostate cancer and correlates with the altered loss of BRCA2 and ATM function, as well as low intratumoral TILs. Therefore, CD276 may be an actionable target for the treatment of this subgroup of prostate cancer [ 98 ].…”