Unraveling the mechanisms of c‐MYC‐mediated escape from antibody and T‐cell based anti‐tumor immune attack in B‐cell malignancies

Background: Overexpression of the c-MYC oncogene (hereafter MYC) was implicated to suppress tumor immune surveillance and shown associate with poor clinical outcome in several malignancies. Here, we investigated its impact on anti-tumor effect antibody T-cell based immunotherapies diffuse large B-cell lymphoma (DLBCL), Burkitt (BL) multiple myeloma (MM). Methods: Using CRISPR-Cas9 gene editing technology, targeted MYC DLBCL cell line OCI-LY18 analyzed 10 randomly selected daughter clones showing partial disruption gene. In one clone repaired DNA sequence by homologous recombination confirm role lysis via NK-cell mediated (rituximab daratumumab) redirecting (blinatumomab) antibodies, target antigen expression apoptosis regulatory proteins. We extended our studies a panel DLBCL, BL MM lines using specific MYC-MAX dimerization inhibitor 10058-F4 study effects immunotherapeutic treatment strategies Results: Rituximab-dependent cellular cytotoxicity (ADCC) significantly increased 9/10 MYC-targeted reversed subclones, illustrating direct involvement modulating rituximab-mediated ADCC (Figure 1A–C). The increase associated upregulation CD20 expression, rituximab 1D–E). targeting also daratumumab-dependent blinatumomab-mediated cytotoxicity, but without their (CD38 CD19, respectively), indicating existence mechanisms beyond modulation expression. depth analyses revealed that appeared upregulate pro-apoptotic PUMA downregulated anti-apoptotic BCL2, XIAP, Survivin MCL-1, attributing development resistance apoptosis, key death mechanism induced NK- T-cells 1F). Furthermore, blinatumomab higher level activation cytokine release response versus parental cells, revealing hitherto unknown suppressive overexpression cells. Finally, efficacy these were improved even primary cells derived from patients after inhibition small molecule 10058-F4, extending results various Encore Abstract - previously submitted regional or national meetings (up <1’000 attendees) Keywords: Aggressive non-Hodgkin lymphoma, Immunotherapy, Tumor Biology Heterogeneity No conflicts interests pertinent abstract.