Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

Abstract

Patients with MYC overexpressing high grade B cell lymphoma (HGBL) face significant dismal prognosis after treatment with standard immunochemotherapy regimens. Recent preclinical studies indicate that MYC not only contributes to tumorigenesis by its effects on cell proliferation and differentiation, but also plays an important role in promoting escape from anti-tumor immune responses. This is of specific interest, since reversing tumor immune inhibition with immunotherapy has shown promising results in the treatment of both solid tumors and hematological malignancies. In this review, we outline the current understanding of impaired immune responses in B cell lymphoid malignancies with MYC overexpression, with a particular emphasis on diffuse large B cell lymphoma. We also discuss clinical consequences of MYC overexpression in the treatment of HGBL with novel immunotherapeutic agents and potential future treatment strategies.

Keywords: MYC; MYC inhibition; T cell therapy; diffuse large B cell lymphoma; high grade B cell lymphoma; immunotherapy; tumor immune evasion.

Figure 1

MYC overexpression is associated with reduced T cell-mediated anti-tumor immune responses and impaired innate anti-tumor immune responses by macrophages and NK cells, but not NK cells with the NKp30 receptor. Top left: simplified summary of adaptive immune responses towards malignant cells with normal MYC expression. Top right: MYC overexpression decreases expression of MHC class I and class II molecules, adhesion and costimulatory molecules. MYC overexpression is associated with reduced cytotoxic T cell responses. Different outcomes on the correlation between MYC overexpression and expression of immune checkpoint programmed death-ligand 1 (PD-L1) have been described. Bottom left: simplified summary of innate immune responses towards malignant cells with normal MYC expression. Bottom right: MYC overexpression reduces NK cell amounts, but not cytotoxicity induced via NKp30 NK cells. MYC overexpression induces expression of immune checkpoint CD47, preventing macrophage (Mph)-induced phagocytosis.

Figure 2

Summary of MYC-dependent regulation of cell metabolism and its effects on the tumor immune environment. MYC stimulates aerobic glycolysis (the conversion of glucose into pyruvate) via glycolytic enzymes TPI, ENO1, PKM2 and HK, and MYC stimulates anaerobic glycolysis (the conversion of glucose into lactate) via LDHA. MYC stimulates glutaminolysis (the conversion of glutamine into glutamate) by inhibiting microRNA-23. Waste products of all three pathways contribute to decreased effector cell cytotoxicity in the tumor immune environment. Green ovals represent enzymes, dark red lines represent inhibitory signals and black arrows represent stimulatory signals. TPI = triose-phosphate isomerase, ENO1 = enolase 1, PKM2 = M2 isoform of pyruvate kinase, TCA = tricarboxylic acid (TCA) cycle, LDHA = lactate dehydrogenase A, TAMs = tumor associated macrophages, GLS = glutaminase, HK2 = hexokinase 2. GLUT1 = glycose transporter 1, SCL1A5 = solute carrier family 1 member 5 (or alanine serine cysteine transporter 2, ASCT2), SLC38A5 = solute carrier family 38 member 5 (or sodium-coupled neutral amino acid transporter 5, SNAT5).

Figure 3

Immunotherapeutic treatment strategies and clinically available MYC modulators in lymphoid malignancies. Antibody-mediated therapies include monoclonal antibodies, antibody-drug conjugates, bispecific antibodies and immune checkpoint inhibitors. Cellular therapies include CAR-T cell therapy and allogeneic stem cell transplantation. Clinically available MYC modulators are lenalidomide (which reduces MYC protein by stimulating Cereblon, subsequently degrading IKZF1 and IKZF3, followed by downregulation of IRF4), idelalisib (PI3K inhibitor) and fimepinostat (combined PI3K and HDAC inhibitor). Preclinical MYC modulators are bromodomain (BRD) inhibitors (e.g., JQ1) and MYC/MAX dimerization inhibitors.