Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy

Figures & data

Figure 1. Immune modulators of the tumor microenvironment that enhance cancer immunotherapy. Different therapies are depicted as described in the text. ATRA, all-trans retinoic acid; IDO, Indoleamine 2, 3-dioxygenase; M1 or M2, M1 or M2 macrophage; MDSC, Myeloid-derived suppressor cell; PD-1, programmed cell death protein 1; TLR, Toll-like receptor

Table1. Examples of strategies for manipulating the tumor microenvironment to enable immunotherapy

Strategy	Microenvironment modifier	Additional immunotherapy	Effect within tumor microenvironment	Effect on tumor size and mouse survival	Ref.
Check point inhibitors	PD-1 and CTLA-4 blockade	Anti-PDL1 plus vaccination with irradiated B16 tumor expressing Flt3L	Increased infiltration of T cells into tumor, IFNγ production, and ratio of effector T cells to MDSCs	65% rejection of s.c. B16 tumors.	^18
	Anti-CD73	ACT of tumor-specific CTL	Enhanced accumulation of effector T cells in tumor, due to restored T cell adhesion and homing.	Delayed tumor growth and enhanced survival of mice bearing s.c. B16-SIY tumors.	^25
Depletion of regulatory cells or inhibition of their suppressive effects	AT38 (blocks peroxynitrite produced by MDSCs)	ACT of tumor-specific CTL	Reduction in intratumoral nitrotyrosines and N-CCL2 expression, enhanced expression of CCL2, induced T cell infiltration.	Rejection of 60% of s.c. EG7-OVA and > 70% of s.c. MCA-203 tumors.	^31
	Treg blockade with anti-CCL1	CpG-ODN	Decreased Treg numbers, increased tumoricidal T cells.	Complete tumor rejection in mice bearing s.c. TUBO tumors.	^29
	IDO inhibitor of Treg suppressive function	IL-12 + GM-CSF microspheres	Transient reduction in Tregs, and increase in ratio of CD8+ to T suppressor cells.	Tumor rejection in 45% of mice bearing metastatic intramammary 4T1 tumors.	^41
Modifying chemokine profile	Oncolytic vaccinia virus expressing CCL5	Tumor lysate-pulsed DCs	Enhanced homing of CD4+ and CD8+ T cells and NK cells, increased IL-12.	Delayed tumor growth of s.c MC38 tumors and enhanced survival of mice.	^69
	Adenovirus expressing CCL16	CpG plus anti-IL-10R antibody	Accumulation of macrophages and DC intratumorally, reversing their immuno-suppression, enhanced TNF and IL-12 production.	Eradication of most tumors in mice bearing s.c tumors of TSA (90%), 4T1 (60%) or MC38 (74%).	^56
Inflammatory mediators and Toll-like receptor agonists	Oncolytic vaccinia virus	Anti-CD137 agonist antibody	Increased infiltration of CD8+, NK cells and neutrophils.	Tumor eradication in > 35% of mice bearing s.c. AT3 tumors.	^77
	HSV-TK retrovirus adhering to T cells	ACT of tumor-specific CTL + gancyclovir + lympho-depletion	Tumor heparanase expression ensured specific delivery of retroviral particles. Maximum number of T cells in tumor occurred at 72–96h.	90% survival of s.c. B16-OVA bearing mice when low numbers of T cells transferred.	^81
Manipulating cytokines	IL-12 transgene in T cells	ACT of tumor-specific CTL + lymphodepletion	Reversed suppression of MDSCs and other immuno-suppressive myeloid cells in tumor.	20–40% survival of mice bearing s.c. B16 tumors.	^96 ^, ^97
	TGF-β inhibitor in liposomal gel (nLG)	IL-2 in nLG	Increased infiltration of NK cells and activated CD8+ T cells	40% survival of mice bearing s.c. B16F10 tumors	^90

A variety of agents can be used to modify the tumor microenvironment as listed. Together with additional immunotherapies, effective anti-tumor responses can be mediated.

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