Combining all-trans retinoid acid treatment targeting myeloid-derived suppressive cells with cryo-thermal therapy enhances antitumor immunity in breast cancer

Abstract

Targeting myeloid-derived suppressive cells (MDSCs) has been considered a potential strategy in tumor therapy. However, a single drug targeting MDSCs remains a challenge in the clinic. An increasing number of studies have shown that combination agents targeting MDSCs and immunotherapy may provide exciting new insights and avenues to explore in tumor therapy. In our previous study, a novel cryo-thermal therapy was developed for metastatic tumors that systematically activate innate and adaptive immunity. Moreover, cryo-thermal therapy was shown to dramatically decrease the levels of MDSCs and induce their differentiation toward potent antigen-presenting cells. However, the therapeutic effects of cryo-thermal therapy on the 4T1 mouse breast cancer model were still not satisfactory because of the high level of MDSCs before and after treatment. Therefore, in this study, we combined cryo-thermal therapy with all-trans retinoid acid (ATRA), a small molecule drug that can induce the inflammatory differentiation of MDSCs. We found that combination therapy notably upregulated the long-term survival rate of mice. Mechanically, combination therapy promoted the phenotype and functional maturation of MDSCs, efficiently decreasing suppressive molecule expression and inhibiting glutamine and fatty acid metabolism. Moreover, MDSCs at an early stage after combination therapy significantly decreased the proportions of Th2 and Treg subsets, which eventually resulted in Th1-dominant CD4+ T-cell differentiation, as well as enhanced cytotoxicity of CD8+ T cells and natural killer cells at the late stage. This study suggests a potential therapeutic strategy for combination ATRA treatment targeting MDSCs with cryo-thermal therapy to overcome the resistance of MDSC-induced immunosuppression in the clinic.

Combining Cryo-Thermal Therapy with Anti-IL-6 Treatment Promoted the Maturation of MDSCs to Induce Long-Term Survival in a Mouse Model of Breast Cancer

“…Then, to investigate the change in MDSCs after cryo-thermal therapy, we analyzed RNA-seq data from previous studies [ 28 ]. Activated signaling pathways were studied using the kyoto encyclopedia of genes and genomes (KEGG) and gene-set enrichment analysis (GSEA), which was based on the NF-κB signaling pathway (mmu04064).…”

“…RNA-seq data were obtained from our previous study [ 28 ]. Gene Set Enrichment Analysis (GSEA) was performed using GSEA software [ 62 ].…”

Metabolic plasticity of T cell fate decision

“…Conversely, glutamine antagonists, such as 6-diazo-5-oxo-l-norleucine (DON), increase the mitochondrial OXPHOS by utilizing FAO, which preserves a greater number of T CM subsets and enhances the ability to effectively eliminate tumors. [58,110,111] Simultaneously, the glutamine antagonist can suppress the oxidative and glycolytic metabolism in cancer cells, consequently reshaping the immunosuppressive metabolic milieu to one that is conducive for bolstering T cell-mediated immunity. These ndings highlight that constitutive activation of glutamine metabolism might serve as a deterrent against CD8 + T cell exhaustion in vivo.…”

Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer

“…This therapy inhibits MDSCs by inducing their differentiation into antigen-presenting cells. However, to improve the in vivo efficacy of this therapy, all-trans retinoid acid (ATRA) is employed to stimulate the maturation of functional MDSCs and inhibit immunosuppressive molecules [ 293 ]. This combination treatment inhibits Th2 and Treg subpopulations while stimulating cytotoxic CD8 + T cells and NK cells to address MDSC-mediated immune tolerance [ 293 ].…”

“…However, to improve the in vivo efficacy of this therapy, all-trans retinoid acid (ATRA) is employed to stimulate the maturation of functional MDSCs and inhibit immunosuppressive molecules [ 293 ]. This combination treatment inhibits Th2 and Treg subpopulations while stimulating cytotoxic CD8 + T cells and NK cells to address MDSC-mediated immune tolerance [ 293 ]. Moreover, MDSC biogenesis may be targeted to reduce MDSC load and enhance immunotherapy response.…”