P802: CD70/CD27 SIGNALING PROMOTES THE EXPANSION OF CLONAL PLASMA CELL SUBSETS IN MULTIPLE MYELOMA
2023-08-01

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Multiple Myeloma (MM) is a hemato-oncological disease characterized by the uncontrolled proliferation of plasma cells in the bone marrow (BM). Although the therapeutic options to treat MM have drastically increased with the introduction of proteasome-inhibitors and immune-modulatory drugs, MM remains an incurable disease. Myeloma cells express several surface antigens that are therapeutically targeted including CD38 or the B-cell maturation antigen. The CD70/CD27 interaction is a classical co-stimulatory signal that induces expansion and effector function of immune cells. However, lymphomas and various solid cancers overexpress CD70. Our lab recently documented that CD70 and CD27 are co-expressed on leukemic stem cells (LSC) and that CD70/CD27 signaling is crucial for LSC self-renewal in acute myeloid leukemia patients. While CD70 is expressed in about 40% of MM patients, no studies have been conducted to investigate the role of CD70/CD27 signaling in MM. Aims: In this study, we analyzed the role of CD70/CD27 signaling in the pathogenesis of MM. The ultimate goal is to design novel treatment strategies to target disease initiating/maintaining MM cells. Methods: We studied the expression of CD70 and CD27 in gene databases, in a newly established MM tissue microarray (TMA) and in a collection of paired BM samples with advanced disease (in collaboration with the Institutes of Pathology in Bern, Basel and Tübingen). To functionally investigate the role of CD70/CD27 signaling, MM cell lines and newly established patient-derived xenografts (PDX) were used. In this regard, xenografts were grown in NOD/SCID (NSG) mice using CD70-expressing MM cell lines and newly established primary samples (EMM01 CD70+). CRISPR/Cas9 genome editing techniques and monoclonal antibodies (Abs) were utilized to specifically abrogate or inhibit CD70-mediated signaling. In this regard, different Abs and Ab-derivates were tested including a CD70 blocking antibody (αCD70) and an antibody-dependent cell-mediated cytotoxicity (ADCC) optimized antibody (cusatuzumab) that activates FcγR-expressing effector cells. Results: The analysis of CD70 gene expression levels from MM patients included in the CoMMpass study revealed that high CD70 gene expression correlates with increased MKI67 gene expression and elevated lactate dehydrogenase (LDH) serum levels suggesting a more rapid proliferation of CD70-expressing myeloma cells. In line, overall survival was significantly worse in CD70 high MM patients. Assessment of the molecular background further revealed increased frequencies of high-risk cytogenetic alterations in CD70 high patients indicating advanced disease stages. A TMA and a longitudinal analysis of matched biopsies from patients at initial diagnosis and MM relapse indicated that CD70 was overexpressed in late/relapsed stages. Functionally, we found that cell-autonomous CD70/CD27 signaling induced proliferation and expansion of MM cell lines and MM cells isolated from patients. Interestingly, CD70 blockade (αCD70) or CD70 knock-out (CD70 KO) resulted in a significant inhibition or complete abrogation of xenograft growth compared to controls (Fig. 1).Summary/Conclusion: Although the treatment options of MM have rapidly increased during the last years, MM remains an incurable disease that ultimately leads to death. Our results indicate that especially advanced MM stages express high levels of CD70. In addition, our results indicate that CD70/CD27 cell-autonomous signaling contributes to disease progression and therapy resistance and identifies CD70 as potential target in MM. Keywords: Multiple myeloma, Myeloma