Clinically feasible approaches to potentiating cancer cell-based immunotherapies

Figures & data

Table 1. Antitumor activities of immune cells

Types of cells	Mechanisms of antitumor action
Mature dendritic cells (DCs)	Immunogenic cross-presentation of TAAs; expression of co-stimulatory molecules such as CD40, CD80, and CD86; production of IFNs, TNF-α, IL-1, IL-4, IL-6, IL-10, IL-12, and IL-23.
Classically activated macrophages (M1)	TAA presentation; expression of co-stimulatory molecules; production of IL-1β and TNF-α; release of ROS and/or RNS; FcR-mediated; ADCC.
Granulocytes	Release of ROS and atopic mediators; production of toxic peptides and IL-4.
Natural killer (NK) cells	Recognition of cells with down-regulated or lost MHC expression; cytotoxicity through perforin and granzymes, and other mechanisms.
B-cells	Immune recognition of soluble and membrane-associated TAAs; TAA presentation; expression of co-stimulatory molecules; generation of plasma cells producing TAA-specific antibodies; complement-dependent cytotoxicity; ADCC.
CD4 T-helper cells	Immune recognition of TAAs bound to MHC class II molecules; contribution to DC and M activation; promotion of NK and NKT cell activation; CTL generation; induction of B-cell differentiation.
CD8 cytotoxic T lymphocytes (CTL)	Immune recognition of TAAs bound to MHC class I molecules; cytotoxicity through effector molecules such as perforin, granzyme B and FasL; production of Th1 cytokines.
ɣδ T cells	Immune recognition of tumor-derived phosphoantigens or stress ligands; contact-dependent cytotoxicity; Th1 cytokine production.
Natural killer T (NKT) cells	Immune recognition through both NK surface receptors and an invariant CD1d restricted TCR; production of IFN-ɣ and IL-4; cytotoxicity mediated by perforin, granzyme B and FasL.

Table 2. Natural and tumor-derived immunosuppression

Immunosuppressive factors	Mechanisms of immunosuppression
T-cell anergy	TCR ligation in the absence of important costimulatory signals.
T-cell exhaustion	Upregulation of both membrane expression of inhibitory molecules and the production of immunosuppressive soluble factors.
Immunosuppressive cytokines and chemokines	Effects on proliferation, differentiation, survival and migration of multiple immune cell lineages.
Immunosuppressive enzymes	Depletion of local tryptophan and arginine levels; production of PGE2.
Tolerogenic DCs	Lack of proinflammatory cytokine production; low level of co-stimulatory molecule expression; production of IL-10 and TGF-β; IDO expression.
Alternatively activated macrophages (M2)	Production of IL-10 and CCL22; expression of PD1L.
Myeloid-derived suppressor cells (MDSCs)	Depletion of arginine; secretion of ROS and RNS; disruption of IL-2 receptor signaling; interference with lymphocyte trafficking; promotion of Treg activation by CD40-CD40L ligation; production of IL-10 and TGF-β.
Regulatory T cells (Tregs)	Expression of inhibitory molecules, such as LAG-3, GITR, CTLA-4, and PD-1; local consumption of IL-2, secretion of IL-10 and TGF-β.
Regulatory B cells (Bregs)	Secretion of IL-10 and TGFβ.
Th1/Th2 imbalance	Reduction of Th1-mediated antitumor immune responses; promotion of alternative M activation and generation of MDSCs.

Table 3. Characteristics of different types of cell-based vaccines

Types of tumor cell vaccines	Characteristics
Autologous vaccines	Full overlapping of vaccine antigens with the antigens of the patient's tumor; no considerable immunogenic activity without adjuvants; limited source of tumor material; no opportunities for standardization or large-scale production.
Allogeneic vaccines	Partial overlapping of vaccine antigens with the antigens of the patient's tumor; no considerable immunogenic activity without adjuvants; limitless source of tumor material; opportunities for standardization and large-scale production.
Xenogeneic vaccines	Partial overlapping of vaccine antigens with the antigens of the patient's tumor; considerable immunogenic activity in the absence of any adjuvant; involvement of natural Abs in cross-presentation by APCs of vaccine antigens; limitless source of tumor material; opportunities for standardization and large-scale production.

Table 4. Immune-based interventions and their mechanisms of action

Types of interventions	Mechanisms of immunomodulatory actions
Cell manipulations (genetic modifications of cellular vaccines; oxidation of TAAs by hypochlorous acid (HOCl); dendritic cell vaccination; adoptive T-cell therapy; NK cell-based immunotherapy)	Enhancement of DC recruitment; enhancement of TAA immunogenicity aiming to break immune tolerance; stimulation of the cross-presentation of TAAs by DCs and other APCs; increase in the frequency of tumor-specific T-cells; upregulation of antitumor immune memory; increase in activity of NK cells.
Non-specific immunomodulators (montanide ISA 51 and 720; alum, QS21; keyhole limpet hemocyanin).	Formation of antigenic depots at the vaccine injection site; augmentation of TAA internalization by APCs; promotion of TAA-specific Th2-mediated immune responses.
TLR agonists (TLR 2, 3, 7/8, and 9).	Promotion of DC maturation and activation; augmentation of tumor-specific Th1-mediated immune responses; activation of NK cells and NKT cells.
Cytokines and chemokines (GM-CSF; Il-12; IL-18; ɣ-chain family of cytokines; IFNs; inflammatory (inducible) and homeostatic (constitutive) chemokines).	Stimulation of DC proliferation and differentiation; recruitment of APCs, T cells and other immune cells to the site of inflammation for Ag processing and presentation, as well as into the tumor microenvironment; induction of MHC expression on tumor cell surfaces; activation of APCs; promotion of Th1 polarization and CTL generation; overcoming T-cell anergy; promotion of expansion of tumor-specific T cells, enhancement of NK cell and CTL activity; induction of classical M activation; contribution to Ab production; stimulation of ADCC.
Hormones and neuromediators (melatonin; thymosin-α; triiodothyronine and others)	Promotion of T cell generation and differentiation; stimulation of DС differentiation.
Immunomodulatory antibodies (immunoactivating antibodies; antibodies blocking coinhibitory signals; antibodies blocking immunosuppressive cytokines).	Activation of APCs; costimulation of tumor-specific T cells; reduction of Treg activity; blockade of coinhibitory signals, blockade of immunosuppressive cytokines.
Depletion/inhibition of immunosuppressive cells (depletion/inhibition of Tregs; depletion/inhibition of MDSCs).	Downregulation of the immunosuppressive activity of Tregs and MDSCs.
Physical treatment (radiation; RFA; HIFU; cryoablation).	Downregulation of tumor cell-mediated immunosuppression; upregulation of the expression of MHC, Fas, ICAM-1, and TAAs on tumor cell surfaces; sensitization of tumor cells to the effector cell-mediated cytotoxicity; enhancement of DC maturation, activation of APCs; reduction in Treg numbers.
Chemotherapy (cyclophosphamide and others)	Reduction in tumor cellmediated mmunosuppression; induction of apoptotic cancer cell death; activation of APCs; sensitization of tumor cells to the effector cell-mediated cytotoxicity; formation of tumor-specific T cell expansion niches in lymphoid tissues; reduction in Treg numbers.
Small molecule-based therapies (Sensitization of tumor cells to apoptosis; inhibition of IDO and/or COX; histamine type-2 receptor antagonists; aptamers; antioxidants).	Induction of apoptotic cancer cell death; activation of APCs; sensitization of tumor cells to the effector cell-mediated cytotoxicity; elevation of tryptophan levels in the tumor microenvironment; reduction of PGE2; blockade of the histamine type-2 receptor; costimulation of T-cell activation; blockade of coinhibitory signals, blockade of immunosuppressive cytokines; decrease in the levels of ROS.

Figure 1. Non-inflamed versus inflamed tumor microenvironments with implications for immunotherapy. Potential barriers to developing antitumor immune responses, and possible contra interventions are indicated for non-inflamed (left) and inflamed tumors (rights). This figure is partially adapted from Spranger S, Gajewski T., 2013 ²⁵.

Spranger S, Gajewski T. Rational combinations of immunotherapeutics that target discrete pathways. J Immunother Cancer 2013; 1:16; PMID:24829752; http://dx.doi.org/10.1186/2051-1426-1-16

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