Update on the challenges and recent advances in cancer immunotherapy

Figures & data

Figure 1 Innate and adaptive immunity in cancer and therapeutic interventions.

Notes: The crosstalk between innate immunity (natural killers [NK], type 1 macrophages [M1], type 1 neutrophils [N1], mature dendritic cells [MDC], immature dendritic cells [IMDC]) and adaptive immunity is illustrated. Antigen (Ag) presentation association to augmentative methods like hyperthermia (HT), radiotherapy (RT), photodynamic therapy (PDT), and chemotherapy (CT) is also illustrated. Further, the important immunosuppressive effects of regulatory T cells (T_reg), myeloid-derived suppressor cells (MDSC), type 2 macrophages (M2) (also called tumor-associated macrophages [TAM]) and the transformation of neutrophils from type 1 with antitumoral capacity versus type 2 (N2), which have angiogenic and pro-tumoral activity are shown. Exosomes, which carry immunosuppressive information, are also depicted. The various treatment methods used to control T_reg, myeloid-derived suppressor cells, and exosomes are in the blue frames, whereas the active treatments with several autologous and allogenic cells cytokine-induced killer [CIK] cells and invariant natural killers [INKT] are illustrated in the green frames. Lymphokine-activated killer [LAK] cells are depicted as “+,” which indicates an augmentative effect, or “−,” which indicates an inhibitory effect.
Abbreviations: ATRA, all-trans retinoic acid; CCL3, chemokine (C-C motif) ligand 3; CD, cluster of differentiation; COX2, cyclooxygenase-2; CTL, cytotoxic lymphocyte; CTLA-4, cytotoxic T-lymphocyte antigen 4; CXCL12, chemokine (C-X-C motif) ligand 12; DCs, dendritic cells; IDC, immature dendritic cells; IL, interleukin; PD-1, programmed cell death protein 1; PGE2, prostaglandin E2; ROS, reactive oxygen species; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.

Table 1 Clinical drugs modulating human myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T_regs) and their mechanism(s) of action

Drug(s)	Cancer	Mechanism(s) of action	PMA	Reference(s)
Vitamin D3	Head and neck	↓ CD34(+), ↑ CD8(+) T cells	D	Lathers et al,^Citation88 Ugel et al^Citation92
ATRA	Renal carcinoma	Induction of differentiation ↓ ROS	D	Mirza et al,^Citation89 Apetoh et al,^Citation90 Ugel et al^Citation92
Sunitinib	Renal cell carcinoma	Prevention of MDSC generation, differentiation mediated by c-kit and transcription factor (STAT3) inhibition	M	Greten et al,^Citation79 Kao et al,^Citation82 Ko et al,^Citation86 Apetoh et al,^Citation90 Ugel et al^Citation92
COX2 inhibitors	Mesothelioma	↓ recruitment of MDSCs	M	Veltman et al,^Citation74 Ugel et al^Citation92
Bevacizumab (anti-VEGF antibody)	Metastatic renal, cervical, colon, mesothelioma	Induction of differentiation toward more mature form of MDSCs	M	Nagaraj and Gabrilovich,^Citation78 van Cruijsen et al,^Citation91 Ugel et al^Citation92
Bisphosphonates		↓ number of MDSCs inside tumor stroma	M	Ugel et al^Citation92
Triterpenoids		↓ IF of MDSCs	F	Apetoh et al^Citation90
Phosphodiesterase-5 inhibitors	Head and neck cancer, myeloma	↓ arginine and NOS expression	F	Apetoh et al,^Citation90 Ugel et al,^Citation92 Nagaraj and Gabrilovich^Citation78
COX2 inhibitors		Downregulation of arginine and NOS expression of MDSCs	F	Ugel et al^Citation92
Docetaxel		Polarization of MDSCs toward M1	F	Apetoh et al^Citation90
Bindarit		↓ CCL2 production, → ↓ recruitment of MDSCs	A	Sevko and Umansky^Citation70
5-FU		↑ depletion of MDSCs, ↑ cell death through inhibition of thymidylate synthase	A	Apetoh et al,^Citation90 Ugel et al^Citation92
Gemcitabine	Pancreatic	↓ number of MDSCs, ↑ (elimination and apoptosis) direct cytotoxicity	A	Martin et al,^Citation13 Apetoh et al^Citation90
*Ipilimumab (CTLA-4)	Melanoma, prostate	↓ number of Tregs, ↓ IF of Tregs		Graziani et al,^Citation99 Singh et al,^Citation105 Hodi et al^Citation106
Tremelimumab	Melanoma	↓ number of Tregs		Reuben et al^Citation115,**
Cyclophosphamide		↓ number of Tregs, ↓ IF of Tregs		Tongu et al,^Citation87 Zou^Citation95
COX2 inhibitors	Breast, lung	↓ IF, ↓ recruitment of Tregs		Karavitis et al,^Citation71 Sharma et al^Citation72
Denileukin diftitox		↓ number of Tregs through inhibition of protein synthesis and ↑ apoptosis		Pere et al^Citation100
*PD-1	Melanoma, renal cell	↓ function of Tregs		Zitovgel and Kroemer,^Citation118 Ménétrier-Caux et al,^Citation119 Topalian et al^Citation120
Daclizumab/basiliximab (anti-CD25 mAbs)	Metastatic breast	↓ of circulating Tregs		Ménétrier-Caux et al^Citation119

Notes:

* PD-1 is better tolerated than CTLA-4;

** clinically ineffective.

Abbreviations: 5-FU, fluorouracil; A, accumulation; ATRA, all-trans retinoic acid; CCL2, chemokine (C-C motif) ligand 2; CD, cluster of differentiation; COX2, cyclooxygenase-2; CTLA-4, cytotoxic T-lymphocyte antigen 4; D, differentiation; F, function; IF, immunosuppressive function; M, maturation; M1, type 1 macrophage; mAbs, monoclonal antibodies; NOS, nitric oxide synthase; PD-1, programmed cell death protein 1; PMA, principal mechanism of action; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor.

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