Monocytic Myeloid-Derived Suppressor Cells Underpin Resistance to Adoptive T Cell Therapy in Nasopharyngeal Carcinoma

Abstract

Advanced, late-stage Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) is incurable, and its treatment remains a clinical and therapeutic challenge. Results from a phase II clinical trial in advanced NPC patients employing a combined chemotherapy and EBV-specific T cell (EBVST) immunotherapy regimen showed a response rate of 71.4%. Longitudinal analysis of patient samples showed that an increase in EBV DNA plasma concentrations and the peripheral monocyte-to-lymphocyte ratio negatively correlated with overall survival. These parameters were combined into a multivariate analysis to stratify patients according to risk of death. Immunophenotyping at serial time points showed that low-risk individuals displayed significantly decreased amounts of monocytic myeloid-derived suppressor cells postchemotherapy, which subsequently influenced successful cytotoxic T-lymphocyte (CTL) immunotherapy. Examination of the low-risk group, 2 weeks post-EBVST infusion, showed that individuals with a greater overall survival possessed an increased frequency of CD8 central and effector memory T cells, together with higher levels of plasma interferon (IFN)-g, and cytotoxic lymphocyte-associated transcripts. These results highlight the importance of the rational selection of chemotherapeutic agents and consideration of their impact on both systemic immune responses and downstream cellular immunotherapy outcomes.

The Stromal and Immune Landscape of Nasopharyngeal Carcinoma and Its Implications for Precision Medicine Targeting the Tumor Microenvironment

“…Differentiated NPC has higher macrophage infiltration, lower B cell infiltration and worse prognosis compared with undifferentiated NPC (39,40). Although Longitudinal analysis has suggested that the peripheral myeloid-to-lymphocyte ratio negatively correlated with overall survival in NPC patients, little is known whether the prognosis is directly influenced by the abundance of macrophages and B cells in the TME (41).…”

Nasopharyngeal Carcinoma and Its Microenvironment: Past, Current, and Future Perspectives

“…An increase in the frequency of MDSCs, and immunosuppressive cytokines, such as CCL2 and CXCL10, underlie the development of resistance towards adoptive immunotherapy. Chemotherapeutic agents, such as gemcitabine and carboplatin may alleviate the resistance by limiting the expansion of MDSCs, secretion of pro-inflammatory cytokines and depletion of immune checkpoint molecules ( 151 ). A phase II study combining chemotherapy with adoptive immunotherapy using engineered EBV-specific CTLs as first-line treatment for metastatic or recurrent NPC patients yield a satisfactory result, with a 2-year OS of 62.9% ( 118 ).…”

Epstein–Barr Virus Epithelial Cancers—A Comprehensive Understanding to Drive Novel Therapies

“…LMP-1 mediated dysregulated glycolysis (through GLUT1), which in turn increases production of IL-1b, IL-6, and GM-CSF, and thus induce myeloid-derived suppressor cells (MDSCs) which are found to be important in T-cell suppression (143). MDSCs are elevated in the NPC TIME and are associated with worse prognosis and resistance to adoptive CTL therapy (144).…”