Blockade of Myeloid-Derived Suppressor Cell Expansion with All-Trans Retinoic Acid Increases the Efficacy of Antiangiogenic Therapy

Abstract

Intrinsic and adaptive resistance hampers the success of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel strategies to improve the efficacy of AAT are warranted. Solid tumors such as breast cancer are characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of resistance to AAT. Therefore, we hypothesized that all- retinoic acid (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. ATRA increased the efficacy of anti-VEGFR2 antibodies alone and in combination with chemotherapy in preclinical breast cancer models. ATRA reverted the anti-VEGFR2-induced accumulation of intratumoral MDSC, alleviated hypoxia, and counteracted the disorganization of tumor microvessels. Mechanistic studies indicate that ATRA treatment blocked the AAT-induced expansion of MDSC secreting high levels of vessel-destabilizing S100A8. Thus, concomitant treatment with ATRA holds the potential to improve AAT in breast cancer and possibly other tumor types. Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment. http://cancerres.aacrjournals.org/content/canres/78/12/3220/F1.large.jpg .

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…The role of MDSC in tumor microenvironment is dual. On the one hand, MDSCs can directly participate in the formation of pre‐metastatic niches and promote the metastasis of tumor cells by infiltrating primary tumors, and promoting tumor angiogenesis by secreting cytokines including TGF‐β, MMP9, vascular endothelial growth factor (VEGF), Bv8, and bFGF; on the other hand, MDSCs can also inhibit immune function to accelerate the tumor progression. Chemokines and related cytokines in tumor microenvironment play a key role in the migration of MDSCs to tumor sites to perform immunosuppressive function.…”

High-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation

“…Myeloid-derived suppressor cells (MDSCs) play essential roles in tumour-induced immune tolerance 14,15 . MDSC expansion in lymphoid organs (the spleen, bone marrow and so on), blood, and tumours has been detected in tumour-bearing mice and cancer patients 16 .…”

Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth

“…It is well known that tRA is a differentiating agent used in the therapy of acute promyelocytic leukemia (APL) therapy, and it is under-used in other malignancies considering its low cost and low systemic toxicity [47][48][49]. In theory, tRA is an ideal candidate for cancer chemoprevention, as cancer is commonly characterized by abnormal growth with a lack of differentiation, which could be modified by tRA, and the combined applications of tRA with other drugs are also in clinical trials [50][51][52]. However, the knowledge of tRA inhibiting angiogenesis is rare, and this limits its usage in cancer therapy.…”