Targeting myeloid-derived suppressor cells for cancer therapy

Hongchao Tang; Hao Li; Zhijun Sun

doi:10.20892/j.issn.2095-3941.2020.0806

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Review | Open Access

Targeting myeloid-derived suppressor cells for cancer therapy

Hongchao Tang^{¹^,^*}, Hao Li^{¹^,^*}, Zhijun Sun^{¹^,²}

()

The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China

Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China

*These authors contributed equally to this work.

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Abstract

The emergence and clinical application of immunotherapy is considered a promising breakthrough in cancer treatment. According to the literature, immune checkpoint blockade (ICB) has achieved positive clinical responses in different cancer types, although its clinical efficacy remains limited in some patients. The main obstacle to inducing effective antitumor immune responses with ICB is the development of an immunosuppressive tumor microenvironment. Myeloid-derived suppressor cells (MDSCs), as major immune cells that mediate tumor immunosuppression, are intimately involved in regulating the resistance of cancer patients to ICB therapy and to clinical cancer staging and prognosis. Therefore, a combined treatment strategy using MDSC inhibitors and ICB has been proposed and continually improved. This article discusses the immunosuppressive mechanism, clinical significance, and visualization methods of MDSCs. More importantly, it describes current research progress on compounds targeting MDSCs to enhance the antitumor efficacy of ICB.

Keywords

Immunotherapy immunosuppression MDSCs ICB compounds

References

Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015; 348: 74-80.

Strategy	Compound	Mechanisms of action	Clinical state	Reference
VPA, valproic acid; CCR2, CC-chemokine receptor 2; ATRA, all-trans retinoic acid; ATX, astaxanthin; WGP, whole β-glucan particles; HDC, histamine dihydrochloride; ADCC, antibody-dependent cellular cytotoxicity; 5-FU, 5-fluorouracil; LPS, lipopolysaccharides; DMBG, dimethylbiguanide; 1-MT, 1-methyl-L-tryptophan; NAC, N-acetylcysteine; WA, Withaferin A.
Preventing the recruitment of MDSCs	AZ13381758 (CXCR2 SM)	Inhibition of CXCR2	Trial in mice bearing pancreatic tumors	⁶⁴
	TG100-115	Inhibition of PI3-kinase isoform p110γ	Trial in mice bearing tumors	⁶⁵
	Zoledronate	Inhibition of MMP-9 activity	FDA approved for multiple cancers	⁸²
	1α,25-Dihydroxyvitamin D3	Inhibition of IL6/p-STAT3	Trial in mice bearing esophageal squamous cell carcinoma	⁸³
	Bevacizumab	Blocking of VEGF signaling	FDA approved for multiple cancers	⁸⁴
	SX-682	Inhibition of CXCR2 signaling	Phase Ⅰ trial in melanoma	⁸⁵
	Sema4D mAb	Inhibition of MAPK-dependent chemokines such as CXCL1, 2, and 5	Trial in mice bearing oral cancer	⁸⁶
	VPA	Inhibition of HDAC activity and downregulation of CCR2	FDA approved for multiple cancers	⁸⁷
Promoting the differentiation of MDSCs into mature cells	Icariin and ICT	Downregulation of S100A8/9, STAT3, and AKT	Phase Ⅰ trial in solid tumors; Phase Ⅲ trial in hepatocellular carcinoma	⁶⁹
	ATRA	Activation of ERK1/2 and upregulation of the ROS scavenger GSH	Phase Ⅱ and Phase Ⅲ trials in multiple cancers; Phase Ⅳ trial in acute promyelocytic leukemia	⁷⁰
	ATX	Activation of the Nrf2 signaling pathway to induce the synthesis of GSH	Early Phase Ⅰ trial in healthy volunteers; trial in mice bearing colon tumors	⁷¹
	Curcumin	Inhibition of activation of NF-κB and STAT3 signaling	Phase Ⅱ and Phase Ⅲ trials in multiple cancers	⁸⁸
	MPSSS	Stimulation of the Myd88-dependent NF-κB signaling pathway	Trial in mice bearing tumor	⁸⁹
	Docetaxel	Decrease in pSTAT3 in MDSCs	FDA approved for multiple cancers	⁹⁰
	WGP	Activation of dectin-1 receptor	Phase Ⅱ trial in non-small cell lung cancer	⁹¹
	HDC	Inhibition of NOX2	Phase Ⅳ trial in acute myeloid leukemia	⁹²
Depleting MDSCs in the circulation and tumor infiltration	Anti-Ly6G mAb; anti-Ly6C mAb	Depletion of MDSCs	Trials in mice bearing multiple types of tumors	⁶¹
	BI 836858	Depletion of MDSCs by ADCC	Phase Ⅰ trial in acute myeloid leukemia	⁷⁴
	Doxorubicin	Triggering of the apoptosis program of MDSCs	FDA approved for multiple cancers	⁷⁵
	Gemcitabine	Induction of MDSC apoptosis and necrosis	FDA approved for multiple cancers	⁷⁶
	5-FU	Activation of caspase-3 and caspase-7 to induce MDSC apoptosis	FDA approved for multiple cancers	⁷⁷
	Celecoxib	Inhibition of COX-2 and decrease in ROS	FDA approved for multiple cancers	⁹³
	RGX-104	Promotion of MDSC apoptosis	Phase Ⅰ trial in malignant neoplasms	⁹⁴
	Anti-IL4Rα aptamer	Inhibition of IL-4Rα–STAT6 signaling	Trial in mice bearing mammary carcinoma	⁹⁵
	Peptibody	Depletion of MDSCs by complement-dependent cytotoxicity or ADCC and induction of MDSC apoptosis	Trials in mice bearing multiple types of tumors	⁹⁶
	DS-8273a	Induction of MDSC apoptosis by agonist of TRAIL-R2	Phase Ⅰ trial in patients with advanced cancers	⁹⁷
Inhibiting the elimination of L-arginine mediated by MDSCs	Phenformin	Decrease in the levels of ARG1 and S100A8/A9	Phase Ⅰ trial in melanoma	⁹⁸
	LPS	Interference with the HMGB1-TLR4 axis	Phase Ⅰ and Phase Ⅱ trials in lymphoma	⁹⁹
	DMBG	Neutralization of the glycosylation function of methylglyoxal	Trial in melanoma-bearing mice	¹⁰⁰
Inhibiting the activation of IDO in MDSCs	Indoximod	Inhibition of IDO	Phase Ⅲ trials in multiple cancers	¹⁰¹
	Navoximod	Inhibition of IDO	Phase Ⅰ trial in patients with recurrent/advanced solid tumors	¹⁰¹
	Epacadostat	Inhibition of IDO	Phase Ⅲ trial in multiple cancers	¹⁰¹
	BMS-986205	Inhibition of IDO	Phase Ⅰ and Phase Ⅱ trials in melanoma; Phase Ⅰ trial in various other types of advanced tumors	¹⁰¹
	1-MT	Inhibition of IDO	Phase Ⅰ and Phase Ⅱ trials in multiple cancers	³⁴
Decreasing the levels of ROS and RNS in MDSCs	Sildenafil	Downregulation of ARG1 and NOS2 expression	FDA approved for multiple cancers	⁷⁸
	CDDO-Me	Inhibition of STAT3 activity, upregulation of antioxidant genes, and decrease in ROS	Phase Ⅰ and Phase Ⅱ trials in multiple cancers	⁸¹
	AT38	Downregulation of ARG1 and NOS2, and decrease in RNS and N-CCL2	Trials in mice bearing multiple types of tumors	³⁹
	NAC	Inhibition of ROS production	Phase Ⅰ trial in multiple cancers; Phase Ⅱ trial in patients at risk of melanoma	¹⁰²
	WA	Decrease in TNFα, IL6, IL10, and ROS	Trials in mice bearing multiple types of tumors	¹⁰³
	Entinostat	Decrease in ARG1, iNOS, and COX2	Phase Ⅰ and Phase Ⅱ trials in multiple cancers; Phase Ⅲ trial in breast carcinoma	¹⁰⁴
	IPI-145	Inhibition of PI3Kδ and PI3Kγ	Phase Ⅰ and Phase Ⅱ trials in head and neck squamous cell carcinoma; Phase Ⅲ trial in lymphoma	¹⁰⁵