Abstract B031: CD27-independent tonic immune checkpoint CD70 signaling provides anti-cancer drug resistance to malignant B cell lymphoma

Abstract CD70 and its ligand CD27 are immune checkpoint molecules that are abnormally expressed in various hematological malignancies. Simultaneous expression of CD70 and CD27 in cancer cells promotes stemness, proliferation, and survival of these malignancies. Moreover, CD70 in cancer cells binds to CD27 in Treg, leading to survival of Treg, which contributes to immune evasion within the tumor microenvironment. We found that the expression of CD70, but not CD27, is induced upon engagement of B cell receptor (BCR). Malignant B cells that harbor constitutively active BCR signaling, therefore, highly expressed CD70 with no correlation of CD27 expression. Interestingly, we found CD70 was a CD27-independent biomarker predicting poor clinical outcomes in diffuse large B-cell lymphoma (DLBCL). To analyze how CD70 independently contributes to malignancy in DLBCL, we generated CD70-deficient DLBCL cells using non-viral CRISPR electroporation. Surprisingly, CD70-deficient lymphoma cells exhibit downregulation of BCL2 family expression, increased apoptosis, and increased sensitivity to vincristine, doxorubicin, and cyclophosphamide. These results indicate that CD70 contributes to chemotherapy resistance independently of CD27. To target the high expression of CD70 that contributes to chemotherapy resistance, we analyzed public Chip-seq data. This analysis revealed that STAT3 acts as a transcription factor for CD70. Consistently, CRISPR-mediated deletion of STAT3 in lymphoma cells dramatically downregulated surface expression of CD70 in parallel with increased anti-cancer drug sensitivity. Therefore, Ruxolitinib, a JAK1/2 kinase inhibitor, leads to decreased CD70 expression by disrupting the JAK-STAT3 signaling pathway, further overcomes chemotherapeutic drug resistance. Ultimately, to effectively eliminate cd70-high malignant b cells that are resistant to conventional chemotherapy, we developed a bike (bispecific nk cell engager) targeting both CD70 and CD16, and testing its immuno therapeutic efficacy. Citation Format: Jaemin Kim, Jaewoong Lee. CD27-independent tonic immune checkpoint CD70 signaling provides anti-cancer drug resistance to malignant B cell lymphoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B031.