Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

Figures & data

Figure 1. How γδ T cells can contribute to the antitumor efficacy of dendritic cell (DC)-based vaccination. It can be postulated that DC vaccination has the ability to activate γδ T cells and initiate their expansion. In turn, activated γδ T cells can (I) further stimulate vaccine and host DCs indirectly supporting sustained antitumor T-cell immunity and NK-DC crosstalk, (II) fulfil their immunomodulatory function through the secretion of pro-inflammatory cytokines regulating innate (natural killer cells) and adaptive (T cells) cellular immunity, and (III) directly kill tumor cells. Abbreviations: CTL, cytotoxic T lymphocyte; DC, dendritic cell; DNAM, DNAX accessory molecule; FASL, Fas ligand; IFN, interferon; IL, interleukin; IPP, isopentenyl pyrophosphate; NK, natural killer cells; TC, tumor cell; TCR, tumor cell; Th1, T-helper 1 cell; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand.

Table 1. Main inhibitory and activating γδ T cell receptors and their ligands

	Receptor on γδ T cells		Ligand(s)
Activating receptors	TCR	–	Both MHC-related and non-related molecules
	CD28	–	CD80/CD86
	CD27	–	CD70
	LFA-1	–	ICAM-1
	CD2	–	LFA-3
	CD6	–	CD166
	CD30	–	CD30L
	NKG2C	–	HLA-E
	NKG2D	–	MICA/BULBP1-6
	CD16	–	Fc portions IgG1, IgG3
	DNAM-1	–	Nectin-like-5, Nectin-2
	NKp30	–	B7-H6, BAT3
	NKp44	–	?
	NKp46	–	?
Inhibitory receptors	PD-1	–	PD-L1
	ILT2	–	HLA-A
	KIR2D	–	HLA-C
	NKG2A	–	HLA-E
	KLRG1	–	Classical cadherins (E-,N-, R-)
	BTLA	–	HVEM, B7H4

Abbreviations: BAT3, HLA-B associated transcript 3; BTLA, B- and T-lymphocyte attenuator; CD, cluster of differentiation; DNAM-1, DNAX accessory molecule-1; HLA, human leukocyte antigen; Ig, Immunoglobulin; HVEM, herpesvirus entry mediator; ICAM-1, intercellular adhesion molecule 1; ILT, immunoglobulin-like transcript; KIR, killer-cell immunoglobulin-like receptor; KLRG1, killer cell lectin-like receptor subfamily G member 1; LFA, lymphocyte function-associated antigen; MHC, major histocompatibility complex; MIC, major histocompatibility complex class I-related chain; NKG, natural killer group; NKp, natural killer cell px-related protein; PD-1, programmed cell death protein 1; TCR, T cell receptor; ULBP, UL16-binding protein.

Table 2. Dendritic cell (DC)-mediated γδ T cell activation

DC-type	Culturing conditions	Effect on γδ T cells	Reference
MHC class II cells (DC)	+ HMBPP or IPP	(+) proliferation	^47
Blood DC	–	(+) proliferation	^41
CD56^+ blood DC	+ zoledronate	(+) proliferation (+) IFN-γ, TNF-α and IL-1β	^10
DC	CD34^+-derived	(+) proliferation	^42
Immature mo-DC	GM-CSF + IL-4	(−) proliferation	^44,48
	GM-CSF + IL-4 + BrHPP	(−) cytotoxicity	^43
	GM-CSF + IL-4 + zoledronate	(+) proliferation	^44
	GM-CSF + IL-4 + zoledronate	(+) IFN-γ and TNF-α	^9
	GM-CSF + IL-4 + zoledronate	(+) killing THP-1	^48
Mature mo-DC	GM-CSF + IL-4 – IL-1β + TNF-α	(−) proliferation	^44
	GM-CSF + IL-4 – IL-1β + TNF-α + zoledronate	(+) proliferation (+) αβ T cell activation	^44
	GM-CSF + IL-4 – TNF-α + IL-1β + IL-6 + PGE2	(−) IFNγ, TNF-α	^9
	GM-CSF + IL-4 – TNF-α + IL-1β + IL-6 + PGE2 + zoledronate	(+) proliferation tumor-antigen specific CD8^+ T cells	^66
	GM-CSF + IL-4 – TNF-α + IL-1β + IFN-α + IFN-γ + poly(I:C)	(+) IFN-γ, TNF-α (+) IL-10	^9
	GM-CSF + IL-4 – MPLA + IFN-γ	(+) IFN-γ, TNF-α	^9
	GM-CSF + IL-4 – TLR-matured	(+) killing Daudi	^9
	GM-CSF+ IL-4 – LPS	(−) killing myeloma cells	^51
	GM-CSF+ IL-4 – LPS + high dose IL-2	(+) proliferation	^51
	GM-CSF+ IL-4 – LPS + low and high dose IL-15	(+) proliferation	^51
	GM-CSF+ IL-4 – LPS + ibandronate	(+) IFN-γ, TNF-α (−) killing myeloma cells	^51
	GM-CSF+ IL-4 – LPS + TNF-α	(−) cytotoxicity	^43
	GM-CSF+ IL-4 – LPS + TNF-α + pamidronate	(+) IFN-γ, TNF-α	^43
	GM-CSF + IL-4 – KLH + IFN-γ + LPS	(−) proliferation CD4^+ and CD8^+ T cells	^67
	GM-CSF + IFN-α	(+) proliferation tumor-specific CD8^+ T cells	^65
Pathogen-infected DC	BCG-DC	(+) proliferation (+) IFN-γ and TNF-α (+) killing THP-1	^48
	Brucella-DC	(+) proliferation CD4^+ T cells	^37
	MTB-DC	(+) proliferation	^49
	HIV-DC	(−) proliferation	^50
pDC	R848-, CpG- or YF-17D-triggered	(+) IFN-γ	^60

Abbreviations: (+), stimulation of γδ T cell function; (−), no effect on γδ T cell function; BCG, Bacillus Calmette-Guérin; BrHPP, bromohydrin pyrophosphate; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; HMBPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; IFN, interferon; IL, interleukin; IPP, isopentenyl pyrophosphate; KLH, keyhole limpet hemocyanin; LPS, lipopolysaccharide; MHC, major histocompatibility complex; mo-DC, monocyte-derived DC; MPLA, monophosphoryl lipid A; MTB, Mycobacterium tuberculosis; pDC, plasmacytoid dendritic cell; PG, prostaglandin; Poly(I:C), polyinosinic-polycytidylic acid; TLR, toll-like receptor; TNF, tumor necrosis factor; YF, yellow fever.

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