Myeloid-derived suppressor cells (MDSCs) constitute a vast population of immature myeloid cells implicated in various conditions. Most notably, their role in cancer is of great complexity. They exert immunosuppressive functions like hampering cancer immunity mediated by T lymphocytes and natural killer cells, while simultaneously they can recruit T regulatory cells to further promote immunosuppression, thus shielding tumor cells against the immune defenses. In addition, they were shown to support tumor invasion and metastasis by inducing vascularization. Yet again, in order to exert their angiogenic activities, they do have at their disposal a variety of occasionally overlapping mechanisms, mainly driven by VEGF/JAK/STAT signaling. In this concept, they have risen to be a rather attractive target for therapies, including depletion or maturation, so as to overcome cancer immunity and suppress angiogenic activity. Even though, many studies have been conducted to better understand these cells, there is much to be done yet. This article hopes to shed some light on the paradoxal complexity of these cells, while elucidating some of the key features of MDSCs in relation to immunosuppression and, most importantly, to the vascularization processes, along with current therapeutic options in cancer, in relation to MDSC depletion.

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of cells with immunosuppressive properties and might confer to worse prognosis in cancer patients. The presence of phenotypically newly described subpopulations of MDSCs and their association with the clinical outcome were investigated in non-small cell lung cancer (NSCLC) patients. The percentages and correlation between MDSCs and distinct immune cells in the peripheral blood of 110 chemotherapy-naive patients before treatment and healthy controls were investigated using flow cytometry. Two monocytic [CD14⁺CD15⁻CD11b⁺CD33⁺HLA-DR⁻Lin⁻and CD14⁺CD15⁺CD11b⁺CD33⁺HLA-DR⁻Lin⁻] and a granulocytic [CD14⁻CD15⁺CD11b⁺CD33⁺HLA-DR⁻Lin⁻] subpopulations of MDSCs were identified, expressing inducible nitric oxide synthase, and reactive oxygen species, respectively. Increased percentages of both monocytic-MDSCs’ subpopulations were inversely correlated to dendritic/monocyte levels(P≤0.04), while granulocytic-MDSCs were inversely correlated to CD4⁺T cells(P=0.006). Increased percentages of monocytic-MDSCs were associated with worse response to treatment(P=0.02)and patients with normal levels of CD14⁺CD15⁺CD11b⁺CD33⁺HLA-DR⁻Lin⁻had longer overall survival and progression free-survival compared to those with high levels(P=0.008andP=0.005, resp.). Multivariate analysis revealed that the increased percentages of CD14⁺CD15⁺CD11b⁺CD33⁺HLA-DR⁻Lin⁻MDSCs were independently associated with decreased progression free-survival and overall survival. The data provide evidence that increased percentages of new monocytic-MDSCs’ subpopulations in advanced NSCLC patients are associated with an unfavourable clinical outcome.

The potential use of plasma-derived small extracellular vesicles (sEV) as predictors of response to therapy and clinical outcome in chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) was explored. sEV were isolated by size-exclusion chromatography from the plasma of 79 chemotherapy-naïve NSCLC patients and 12 healthy donors (HD). sEV were characterized with regard to protein content, particle size, counts by qNano, morphology by transmission electron microscopy, and molecular profiles by Western blots. PD-1 and PD-L1 expression on circulating immune cells was analysed by flow cytometry. Pre-treatment levels of total sEV protein (TEP) were correlated with overall (OS) and progression-free survival (PFS). The sEV numbers and protein levels were significantly elevated in the plasma of NSCLC patients compared to HD (p = 0.009 and 0.0001, respectively). Baseline TEP levels were higher in patients who developed progressive disease compared to patients with stable disease (p = 0.007 and 0.001, stage III and IV, respectively). Patient-derived sEV were enriched in immunosuppressive proteins as compared to proteins carried by sEV from HD. TEP levels were positively correlated with CD8⁺PD-1⁺ and CD8⁺PD-L1⁺ circulating T cell percentages and were independently associated with poorer PFS (p < 0.00001) and OS (p < 0.00001). Pre-therapy sEV could be useful as non-invasive biomarkers of response to therapy and clinical outcome in NSCLC.

The aim of this study was to investigate the best administration of telomerase reverse transcriptase (TERT₅₇₂), an human leukocyte antigen-A*0201-restricted cryptic epitope of telomerase, and its optimized variant TERT_572Y to elicit specific T cell immune responses in cancer patients. Forty-eight cancer patients with chemo-resistant tumors received 2 subcutaneous injections of TERT_572Y at 2 mg followed at random by 4 subcutaneous injections of either TERT₅₇₂ or TERT_572Y peptides at 2 mg every 3 weeks. Specific immune response was evaluated by interferon-γ enzyme-linked immunosorbent spot. T cell responses after the sixth vaccination were detected more frequently (44% vs. 17%), and with higher number of peptide-specific reactive T cells (60 T cells/2×10⁵ peripheral blood mononuclear cell vs. 10 T cells/2×10⁵ peripheral blood mononuclear cell, P=0.04), and higher avidity in the patients who received 4 more vaccinations with the TERT₅₇₂ peptide compared with patients who received only TERT_572Y vaccinations. These results demonstrate that the best vaccination schedule involves first the administration of the optimized TERT_572Y followed by the native TERT₅₇₂ peptides in patients who are candidates for cancer immunotherapy.

Osteosarcoma (OS), the most common primary bone cancer of mesenchymal origin in children and young adolescents, remains a challenge due to metastasis and resistance to chemotherapy. It displays severe aneuploidy and a high mutation frequency which drive tumor initiation and progression; however, recent studies have highlighted the role of epigenetic modifications as a key driver of OS pathogenesis, independent of genetic mutations. DNA and RNA methylation, histone modifications and non-coding RNAs are among the major epigenetic modifications which can modulate the expression of oncogenes. Abnormal activity of these mechanisms contributes to gene dysregulation, metastasis and immune evasion. Therapeutic targeting against these epigenetic mechanisms, including inhibitors of DNA and RNA methylation as well as regulators of RNA modifications, can enhance tumor suppressor gene activity. In this review, we examine recent studies elucidating the role of epigenetic regulation in OS pathogenesis and discuss emerging drugs or interventions with potential clinical utility. Understanding of tumor- specific epigenetic alterations, coupled with innovative therapeutic strategies and AI-driven biomarker discovery, could pave the way for personalized therapies based on the molecular profile of each tumor and improve the management of patients with OS.