Table 1.

Summary of the main immunomodulating effects of immunomodulatory drugs (IMiDs), proteasome inhibitors, histone deacetylase inhibitors, cyclophosphamide, arginase inhibitors and IDO inhibitors.

Drug Group	Drug Name	Target Cell Population	Immune Effects/Molecular Mechanisms	Reference
Immunomodulatory drugs (IMiDs)	Thalidomide	T cells	↑ cytotoxic responses	[155]
			↑ proliferative responses ↑ IL-2 and IFN-γ	[155,156]
		NK cells	↑ cytotoxic activity	[156]
	Lenalidomide	T cells	↑ IL-2 production	[157,158]
			↑ AP-1 transcriptional activity	[157]
			↑ activation; ↓ Ikaros and Aiolos	[159]
		NK cells	↑ cytotoxic activity	[158]
		PBMCs	↑ cytotoxic activity	[159,160]
			↑ ADCC	[158]
		MM cells	↑ MICA and PVR expression	[161]
			↓ PD-L1 expression	[35,162]
			No change in PD-L1 expression	[163]
		DCs	↑ endocytic activity ↑ MHC Class I and CD86 expression	[164]
		Treg	↓ proliferation	[165]
			↓ differentiation	[166]
	Pomalidomide	T cells	↑ IL-2 production	[157,158]
			↑ AP-1 transcriptional activity	[157]
			Nuclear translocation of AP-1 and NFAT2	[158]
		NK cells	↑ granzyme-B expression	[167]
			↑ cytotoxic activity	[158,167]
			↑ Zap-70 phosphorylation	[167]
		PBMCs	↑ ADCC	[158]
		MM cells	↑ MICA and PVR expression	[161]
			↑ CD38 expression	[168]
		DCs	↑ endocytic activity ↑ MHC Class I and CD86 expression	[164]
		Treg	↓ proliferation	[165]
Proteasome inhibitors(PIs)	Bortezomib	Tumor cells	↑ Hsp60 and Hsp90 exposure (↑ ICD induction)	[169,170]
		MM cells	↑ CALR exposure (↑ ICD induction)	[171]
	Carfilzomib	MM cells	↑ CALR exposure (↑ ICD induction)	[171]
Histone deacetylase inhibitors (HDACi)	MGCD0103 (mocetinostat)	MM cells	↑ susceptibility to lysis by MAGE-A3-specific CTLs	[172]
	Valproic acid (VPA)	MM cells	↑ MICA/B and ULBP2 expression	[173]
	Sodium butyrate	MM cells	↑ MICA expression	[174]
	Panobinostat	MM cells	↑ ULPBP2/5/6 and MICA/B expression	[163]
			↑ PD-L1 expression	[163]
			↑ CD38 expression	[175]
		DCs	Impairment of DCs function to stimulate antigen-specific immune responses	[176]
	ACY-241	DCs	↓ PD-L1 expression (pDCs) ↑ CD80, CD86 and MHC molecules (Class I and II) expression	[177,178]
		MM cells	↓ PD-L1 expression ↑ CD80, CD86 and MHC molecules (Class I and II) expression	[178]
			↑ CD38 expression	[179]
		Treg	↓ PD-L1 expression	[178]
		T cells	↓ PD-1 expression	[178]
	Entinostat	MM cells	↑ PD-L1 expression	[163]
			↑ CD38 expression	[180]
	Ricolinostat	MM cells	↑ PD-L1 expression	[163]
			↑ CD38 expression	[179]
	WT-161	MM cells	↑ CD38 expression	[179]
Alkylating agents	Cyclophosphamide	Tumor cells	↑ CALR translocation	[181,182]
			↑ release of HMGB1	[181]
		Tregs	Depletion of this population	[182,183]
		T cells	Promotes Th1 polarization	[183]
		NK cells	↑ activation	[182]
		Myeloid cells	Modulation of this population	[182]
		MM cells	↑ secretory response, ↓ CD47	[184]
		Macrophages	↑ CD64 expression, ↑ ADCP	[184]
Arginase inhibitors	nor-NOHA	High-density neutrophils	Reversion of the immune-suppressive properties of this population	[103]
	CB-1158	High-density neutrophils	Reversion of the immune-suppressive properties of this population	[103]
	BEC	M2-type macrophages	Reversion of the anti-myeloma effect of M2-type macrophages in the context of Th2 adoptive cell therapy	[185]
		MDSCs	Reversion of the inhibitory effect of conditioned media from MDSCs on the anti-myeloma efficacy of bortezomib	[102]
IDO inhibitors	INCB014943	DCs	Reversion of effector T cell suppression induced by DCs	[74]
	1-methyl-DL-Trp	IDO+ MM cells	Reversion of Treg expansion induced by IDO	[186]
		Osteoclasts	Reversion of the suppression of T-cell proliferation and CTLs activity induced by osteoclasts	[187]
		Macrophages	Reversion of the inhibition of CD4+ T cell proliferation and cytokine production induced by macrophages	[188]