MYC inhibition reprograms tumor immune microenvironment by recruiting T lymphocytes and activating the CD40/CD40L system in osteosarcoma

Abstract

The efficacy of immune checkpoint blockade (ICB) therapy depends on sufficient infiltration and activation of primed tumor-specific cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. However, many tumor types, including osteosarcoma, mainly display immune-desert or immune-excluded phenotypes, which are characterized by a lack of tumor-infiltrating lymphocytes and a poor response to ICB monotherapy. Thus, novel therapeutic strategies are urgently needed to surmount these obstacles. In this study, we found that the expression of the c-Myc oncogene is negatively correlated with the T cell infiltration rate in osteosarcoma. Pharmacological inhibition of c-Myc with JQ-1 significantly reduced tumor burden and improved overall survival in an immunocompetent syngeneic murine model of osteosarcoma (K7M2). A mechanistic study revealed that JQ-1 administration dramatically reprogrammed the tumor immune microenvironment (TIME) within K7M2 tumors. On the one hand, JQ-1 can promote T cell trafficking into tumors by increasing the expression and secretion of T cell-recruiting chemokines. On the other hand, JQ-1 is capable of facilitating crosstalk between antigen-presenting dendritic cells and T cells through the CD40/CD40L costimulatory pathway, leading to activation of tumor-specific CTLs. Combined treatment with anti-PD-1 antibody and JQ-1 resulted in more pronounced tumor regression than either monotherapy, showing an obvious synergistic effect. These findings uncover for the first time that c-Myc inhibition can promote T cell infiltration and activation in osteosarcoma in multiple ways, delivering a one-two punch for modulating TIME. The present work also provides the basis for establishing c-Myc inhibitor and ICB coadministration as a novel therapeutic regimen for patients with osteosarcoma.

Tumor Growth Remains Refractory to Myc Ablation in Host Macrophages

“…Myc expression in TAMs has been shown to regulate tumor growth by reinforcing an immunosuppressive microenvironment [ 13 , 14 , 30 ], while the inhibition of Myc enables T-cell-mediated immune surveillance [ 31 , 32 ]. We therefore profiled tumors from Gp130 F/F , KPT, B16F10, or MC38 models that arose in either LysM +/+ ; Myc fl/fl or LysM Cre/+ ; Myc fl/fl hosts for markers associated with immune suppression (i.e., Il4 , Il10 , Il13 , Arg1 , Ym1 , Mrc1 , Tgfβ ) and immune activation (i.e., Il1β , Il12 , Tnfα , Nos2 , Ifnγ , GzmB and Prf1 ).…”

Subtype Classification and Prognosis Signature Construction of Osteosarcoma Based on Cellular Senescence-Related Genes

“…MYC activation induces the expression of p16 (INK4a) and p21 (Cip1) and resulted in Cdk2-deficient CS [ 31 ]. Inhibition of MYC reprograms TME by recruiting T lymphocytes and activating the CD40/CD40L system in osteosarcoma [ 32 ]. Overexpressed distal-less homeobox 2 (DLX2) is associated with adverse clinical outcomes in hepatocellular carcinoma [ 33 ] and gastric adenocarcinoma [ 34 ].…”

Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation

“…In addition, the CD40/CD40L immune checkpoint pathway, which rescues tumour cells from apoptosis, prolongs survival and enhances the proliferation, activation, or maturation of APCs, including primarily macrophages and DCs, to produce IL-12 or IL-18 to stimulate NK cells. These, in turn, produce IFN-γ and express co-stimulatory molecules, such as CD80/CD86, ICAM-1, and CD44, which are required for the non-energetic full activation of T cells following T cell receptor stimulation [ 281 , 282 ].…”