Table 2.

Strategies of targeting IL-8/IL-8Rs in therapies of CM and other neoplasms.

Target	Therapeutic Strategy	Impact	Experimental Approach	References
IL-8	mAb anti h-IL-8 (ABX-IL8)	Neutralize secreted IL-8; inhibit invasion, MMP-2 secretion, decrease vascularization	Human melanoma and animal models	[133]
	IL-8 neutralizing Abs IL-8 downregulated	Disorients DC migration, without impairing T-cell stimulation	Colon cell carcinoma tumors	[119]
IL-8Rs (CXCR1/2)	Inhibitors
	Low-molecular-weight antagonists, modified chemokines, antibodies directed against receptors	Inhibit tumor growth and angiogenesis	Human melanoma tumors in athymic nude mice	[196]
	Antagonists to CXCR2	Promotes tumor progression in vivo by impeding DC activation or recruitment	Colorectal cancer subtype	[208]
	Ladarixin	Abrogates tumor cell motility, self-renewal, intratumor de novo-angiogenesis; induces apoptosis, polarizes M1 TAMs	Melanoma cells, xenografts and tumors	[198]
	Reparixin	Reducing cancer stem cells by targeting their CXCR1	Breast cancer clinical trial phase 3	[197]
COMBINATORIALS IL-8/IL-8Rs agonists, mAbs, gene downregulators, tumor specific pathways/key molecules, chemotherapeuticals, immune cell modulators	Braf inhibitor/vemurafenib; MEK1/2 inhibitor/ trametinib	Decrease IL-8 and suppress tumor evolution	Melanoma cell subpopulations	[199]
	mAb (ABX-IL8) + MUC18 + DITC	Overcome resistance to chemotherapy and improve survival of patients	Metastatic melanoma	[194]
	Si-IL-8 treatments + docetaxel	Downregulate IL-8 and potentiate chemotherapeutic agents	Ovarian tumor xenografts	[195]
	mAbs anti-PD1/PD-L1- (nivolumab, pembrolizumab, atezolizumab) + mAbs antiCTLA-(Ipilimumab)	Tumor burden changes	Patients with melanoma and NSCLC	[206]
	Reparixin + paclitaxel	Increases tumor sensibility to chemotherapy	HER-2 negative metastatic breast cancer	[211]
	Inhibitors of CXCR1/2 + CXCL12/CXCR4 or CCR5	Hinder recruitment of neutrophils in tumor microenvironment	Metastatic colorectal cancer	[213]
	mAb anti-CD40 + gemcitabine; PI3Kg inhibitors+ nivolumab	Increases pro-inflammatory gene expression in TAMs, reprogramming of M2 to pro-inflammatory M1 phenotypes, anti-tumor activity	Pancreatic ductal carcinoma	[215]
	Synergistic PI3K/mTOR and JAK2 /STAT5 inhibition	Reduced cancer cell number and tumor growth, decreased tumor seeding, metastasis, increased overall survival of the animals.	Breast cancer	[170]

Abreviations: mAb—monoclonal antibody; BM—basement membrane; DITC—dacarbazine; NSCLC—non-small cell lung cancer; MDSCs—myeloid-derived suppressor cells; DCs—dendritic cells; PMNs—polymorphonuclear neutrophils; TANs—tumor associated neutrophils.