Tumor associated macrophages as key contributors and targets in current and future therapies for melanoma

Figures & data

Figure 1. Macrophages can be polarised to a pro-tumour phenotype by cells in the TME. Macrophages can be influenced by melanoma-secreted factors, melanoma-derived exosomes and melanoma-derived products of hypoxia metabolism. Regulatory T cells (Treg) can reduce IFNγ production, required for pro-inflammatorymacrophage polarisation, as well as produce immunoregulatory cytokines including TGFF-β, IL-10 and IL-4. Effector T cells (Teff) and macrophages can interact via the PD-1/PD-L1 axis, reducing T cell activation and further promoting an immunoregulatory environment. B cells can secrete multiple immunoregulatory factors that influence macrophage states; and pro-tumour neutrophils reciprocally interact with macrophages to increase the recruitment and polarisation of both pro-tumour macrophages and neutrophils. Created with BioRender.com

Table 1. Examples of current and ongoing clinical trials targeting macrophages in cancer therapy.

Drug Name	Type	Target	Cancer Type	Phase	Status	Route of Drug Administration	Outcome	Reference
Plozalizumab Vedolizumab	mAb – IgG1	CCR2	Melanoma	1b	Terminated	Intravenous	Protocol efficacy futility met	NCT02723006
Carlumab	mAb – IgG1	CCL2	Solid tumors	1	Completed	Intravenous	No objective anti-tumor response observed	NCT00537368
Sotigalimab	mAb – IgG1	CD40	Solid tumor	1b	Active	Intravenous		NCT03502330
CP-870,893	mAb – IgG2	CD40	Melanoma	1	Completed	Intravenous	Combination therapy shows clinical efficacy	NCT01103635
Cabiralizumab	mAb – IgG4	CSFR-1	Solid tumor	1b	Active	Intravenous		NCT03502330
Emactuzumab	mAb – IgG1	CSFR-1	Solid tumors	1/1b	Active	Intravenous		NCT01494688
Emactuzumab	mAb – IgG1	CSFR-1	Solid tumors	1	Completed	Intravenous	Manageable safety profile and considerable objective response rate was observed	NCT02323191
Poly-ICLC	dsRNA	TLR3	Solid tumor	1	Active	Intratumoral		NCT04116320
BO-112	dsRNA	TLR3	Melanoma	2	Active	Intratumoral		NCT04570332
Bevacizumab	mAb – IgG1	VEGF	Melanoma	2	Recruiting	Intravenous		NCT04356729
AT13148	Protein kinase inhibitor	ROCK-AKT	Solid tumor	1	Completed	Orally	No results published	NCT01585701
Vactosertib	Protein kinase inhibitor	TGF-β	Melanoma	2	Recruiting	Orally		NCT05436990
Panobinostat	Hydroxamic acid	HDAC	Melanoma	1	Completed	Orally	Results pointed against the use as monotherapy	NCT01065467
Panobinostat	Hydroxamic acid	HDAC	Melanoma	1	Completed	Orally	No additional benefit observed in response rate when combined with anti-CTLA4	NCT02032810
0508CT-	CAR-M	HER-2	Solid tumors	1	Recruiting	Intravenous		NCT04660929

Figure 2. Harnessing macrophages to enhance current and future therapies. Macrophages can be harnessed to hone an anti-tumour immune response via several therapeutic strategies. The left side summarises approaches to inhibit macrophages and their pro-tumour functions. Top left: treatment approaches blocking recruitment and survival of macrophages. Bottom left: strategies focusing on inhibiting immunosuppressive functions of macrophages and re-educating TAMs into anti-tumour effectors. The right side summarises current treatment approaches that stimulate a pro-inflammatory TAM response, including stimulation through multiple cell-surface receptors and the creation of CAR-M with enhancing cancer killing abilities. Created with BioRender.com