Improving immunotherapy in high-grade B-cell lymphoma

MYC is a transcription factor that upon deregulation acts as an oncogene. Cancer patients with MYC overexpression face significant worse outcomes to treatment with (immuno)chemotherapy. In this thesis, we investigated MYC’s impact on the efficacy of novel immunotherapeutic approaches in aggressive B-cell non-Hodgkin lymphomas (NHL) and explored strategies to improve cancer immunotherapy. In Part I, we introduced MYC and its oncogenic functions. In Chapter 1 we provided a general introduction to the biological significance of MYC in B-cell NHL and addressed clinically available immunotherapeutic approaches, including rituximab-based immunochemotherapy and upcoming (second-line) bispecific T cell engagers, chimeric antigen receptor (CAR)-T cell therapy, and immune checkpoint inhibitors. In Chapter 2 we reviewed the impact of MYC on innate and adaptive immune responses in B-cell lymphoid malignancies, including impaired immune surveillance by reducing antigen presentation through downregulation of HLA class II molecules and hindering T cell recognition and activation by downregulating adhesion and costimulatory signal. While MYC is associated with increased PD-L1 expression in some cancers, its role in lymphomas remains inconsistent. Although these data provided critical insights into the effects of MYC on innate and adaptive immune responses, the mechanism underlying resistance to immunochemotherapy by MYC overexpression remains unclear. Therefore, in Part II, we explored the mechanisms by which MYC enables lymphomas to escape immunotherapy. In Chapter 3, we delineated lymphoma-intrinsic mechanisms through which MYC mediates resistance to conventional and T cell redirecting antibodies. We pharmacologically and genetically inhibited MYC in vitro and ex vivo and discovered that MYC downregulates target antigen expression of rituximab (CD20), but not of other conventional (daratumumab) or bispecific T cell engaging (blinatumomab) antibodies. Additionally, MYC downregulation triggered apoptotic pathways and increased T cell activation in response to blinatumomab. Given the toxicity of direct MYC inhibition, modulating MYC-mediated immune evasion may improve immunotherapy outcomes. To investigate the effect of MYC on the lymphoma-immune microenvironment (LIME), we compared the LIME of HGBL-MYC and DLBCL not otherwise specified (NOS) in Chapter 4. In Chapter 5 we profiled the peripheral T and NK cells, and showed that HGBL-MYC is associated with exhausted CD8+ T cells, while DLBCL NOS shows more senescent T cells. Thus, oncogenic MYC may impair immunotherapeutic approaches via lymphoma-intrinsic mechanisms and effects on the (peripheral) immune microenvironment. In Part III, we proposed strategies to enhance immunotherapeutic approaches in MYC-rearranged lymphomas. In Chapter 6 we found that a MYC rearrangement worsens prognosis in stage II but not stage I DLBCL, providing clarity on the distinct prognostic implications of a MYC rearrangement in early-stage disease and addressing the importance of MYC in stage II and above. In light of these results, this thesis concentrated on stage II-IV DLBCL/HGBL-MYC. In this cohort of patients, we conducted two clinical intervention studies. Chapter 7 we described a non-randomized comparison of the immunomodulatory drug lenalidomide plus R-CHOP (R2CHOP) versus R-CHOP alone for treating MYC-rearranged DLBCL. Three statistical analyses consistently showed improved outcome after R2CHOP, leading to R2CHOP’s inclusion in Dutch clinical guidelines as an alternative to DA-EPOCH-R for HGBL-MYC. In Chapter 8 we presented the first phase II study on nivolumab consolidation, a monoclonal anti-PD-1 antibody, in patients in CMR after induction treatment with DA-EPOCH-R. The results suggest a role for immune checkpoint inhibitors but highlight the need for better induction regimens. In Chapter 9 we found that response to DA-EPOCH-R is associated with the activation of “fitter”, less exhausted cytotoxic T cells over time, informing potential treatment optimization. Overall, this thesis enhances our understanding of MYC’s role in escape from immunotherapeutic approaches and therapy resistance. We provide novel insights and potential strategies to improve immunotherapy outcomes for patients with high-grade B-cell lymphomas.