Dendritic Cell Vaccines for Cancer Immunotherapy

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1		Maria Teresa Cruz	+ 2981 word(s)	2981	2022-03-10 07:06:15	\|
2	format correction	Peter Tang	Meta information modification	2981	2022-03-18 12:18:36	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics12020158

Dendritic cells (DCs) are a class of bone-marrow-derived cells present in blood, epithelial, interstitial and lymphoid tissues, originated from lympho-myeloid hematopoiesis through a series of differentiation processes. Throughout the last decades, DC-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response.

conventional type 1 dendritic cells CD141+XCR1+ DCs dendritic cell-based vaccines anti-tumor immunotherapy

1. Introduction

The manipulation and education of the immune system for targeting and eliminating cancer cells has been viewed as a crucial goal of cancer therapy for decades ^[1]^[2]^[3]. The recent introduction of monoclonal antibodies (mAbs) blocking immune checkpoint molecules, such as programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), in clinical practice, has been a clear success, highlighting the potential of immunotherapy in the oncology field ^[4]^[5]. Additionally, strategies directly using immune cellular effectors, such as activated natural killer (NK) cells, chimeric antigen receptors (CAR) T-cells, tumor-infiltrating lymphocytes (TILs) and tumor antigen-loaded dendritic cells (DCs), have been used to boost anti-tumor immunity, with promising results ^[6]^[7]^[8]^[9].

DCs have been clinically used for three decades, with more than 300 completed or ongoing registered clinical trials conducted to test their application for boosting anti-tumor immunity ^[10]. DCs are a heterogeneous population of hematopoietic cells acting on the articulation between adaptive and innate immunity ^[11]. They comprise several subsets with distinct phenotypical and functional capacities, distributed across the blood, skin, mucosa and lymphoid tissues. Moreover, they are proficient, displaying an unparallel capacity to acquire, process and present antigens to naïve T cells, polarizing them into effector or tolerogenic subsets ^[11]^[12]^[13]. Therefore, these cells orchestrate adaptive immune responses by promoting either immunity to foreign antigens or tolerance to self-molecules ^[14].

Currently, there are four approaches for exploring DCs in cancer immunotherapies: (1) non-targeted protein and nucleic acid-based vaccines; (2) antigens targeting endogenous DCs; (3) ex vivo generated DCs matured and loaded with tumor antigens; and (4) biomaterial-based platforms for the in situ recruitment and reprogramming of endogenous DCs ^[15]^[16]. Among the registered clinical trials performed with DC-based anti-tumor vaccines, the most common approach relies on the use of ex vivo differentiated DCs from leukapheresis-isolated CD14⁺ monocytes (MoDCs), cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) ^[10]. Although the gathered data shows evidence that these DC vaccines are well-tolerated and present a good safety profile, clear therapeutic outcomes are achieved in less than 15% of patients ^[6]^[10]. The common tumor-associated immune suppression in enrolled late stage patients, the tumor antigens chosen as targets and the limited functional abilities of MoDCs are some of the factors that explain this lack of efficacy ^[17]^[18]. In fact, in vitro generated MoDCs underperform in key aspects that are determinant for a successful clinical outcome, such as their ability to migrate from the injection sites towards lymph nodes and their capacity to effectively elicit strong cytotoxic T lymphocyte (CTL) responses ^[19]^[20]^[21]^[22]^[23]^[24]. As an alternative, natural circulating DCs (nDCs), despite their scarce presence in the blood, display many advantages that make them an attractive source for cancer immunotherapy.

2. Development, Regulation and Heterogeneity of cDC1

Ontogeny studies on murine models are beginning to unravel the development of DC subsets; however, the translation of these discoveries to human biology is not always straightforward ^[25]. Human DCs develop from multipotent hematopoietic stem cells (HSCs) primed by predestined-related but distinct pathways of lympho-myeloid hematopoiesis, which share a common transitory phenotype and differentiate into specific subsets by the influence of lineage-specific transcription factors, particularly IRF8 and IRF4 ^[26]^[27]. Contemporary models of lympho-myeloid hematopoiesis place the lymphoid-primed multipotent progenitors (LMPP) at the apex of all myeloid and lymphoid lineages, separated from megakaryocyte and erythroid potential (MkE) ^[26]. Located in the bone marrow, this precursor differentiates into the granulocyte macrophage DC progenitor (GMDP), with the potential to generate granulocyte, macrophage and DC populations ^[26]^[28]. A phenotype shift occurs when these progenitor cells start to express CD115 (M-CSFR), giving rise to macrophage DC progenitors (MDPs). Subsequently, MDPs increase the expression of CD123 and differentiate into CDPs (common DC progenitors) with the capacity to exclusively generate all three DC subsets ^[26]^[28]^[29]. Whereas pDCs terminally differentiate in the bone marrow, DC-restricted precursors not fully expressing the phenotype of differentiated DCs, termed pre-cDCs, migrate through the blood to lymphoid and non-lymphoid tissues, where they produce cDC1 and cDC2 (Figure 1) ^[29]^[30]^[31]^[32].

Figure 1. Schematic representation of cDC1 DC development. In the bone marrow, HSC gives rise to the LMPP, which settles at the apex of all myeloid and lymphoid lineages and is separated from the MkE. GMDP derives from the LMPP and produces the MDP (expressing M-CSFR), which further differentiates into the CDP, capable of generating the main DC subsets: pDCs, cDC1 and cDC2. pDCs terminally differentiate in the bone marrow, whereas pre-cDC migrate through the blood to lymphoid and non-lymphoid tissues, where they produce cDC1 and cDC2 subsets. Determining the differentiation pathway, Notch-dependent interactions of CDPs with stromal cells, in cooperation with GM-CSF, are crucial for the commitment to the cDC1 lineage, separating their pathway from pDCs. In peripheral tissues, the differentiation into CD141⁺ cDC1 is controlled by transcription factors, such as IRF8, Batf3 and Id2 (shown in blue). After engagement with the CD141⁺ pathway, the existence of a two-staged differentiation process of cDC1 populations is proposed, in which XCR1-negative cDC1s under the influence of GM-CSF (shown in red) acquire the expression of XCR1, representing the shift between a pre-cross-presentation phase and a subsequential cross-presenting stage. cDC, conventional dendritic cell; CDP, common DC precursor; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; GMDP, granulocyte macrophage DC progenitor; HSC, hematopoietic stem cell; LMPP, lymphoid-primed multipotent progenitor; M-CSFR, macrophage colony-stimulating factor receptor; MDP, macrophage DC precursor; MkE, megakaryocyte and erythroid potential; pDC, plasmacytoid dendritic cell.

cDC1 population development is under the control of a set of key transcription factors, namely IRF8, BATF3, GATA2, PU.1, GFI1 and Id2 ^[26]^[33]^[29]^[34]^[35]. In accordance, a recent work demonstrated that the concomitant expression of PU.1, IRF8 and BATF3 transcription factors is sufficient for reprogramming both mouse and human fibroblasts so that they acquire a cDC1-like phenotype ^[36]. Other in vitro experiments have shown that FMS-like tyrosine kinase 3 ligand (Flt3L), GM-CSF, Stem cell factor (SCF), thrombopoietin (TPO), IL-6, IL-3 and IL-4 might play a role in cDC1 differentiation from human CD34⁺ progenitors ^[25]^[29]^[37]. Finally, Notch signaling, especially in cooperation with GM-CSF, is crucial for promoting the in vitro differentiation of cDC1 from CD34⁺ progenitors ^[38]; by blocking the Notch pathway at different time points, it was shown that its signal was particularly important in the beginning of the differentiation process ^[38]. These data point out the existence of Notch-dependent lineage bifurcation that separates pDCs and cDC1 pathways from their CDP. Notch-dependent interactions of DC precursors with stromal cells were also proposed to determine the commitment to the cDC1 lineage ^[38].

cDC1 are approximately ten times less abundant than cDC2, being present in the blood, lymph nodes, tonsils, spleen, bone marrow and non-lymphoid tissues, such as the skin, lung, intestine and liver ^[26]^[25]^[39]. This DC subset is characterized by a high expression of CD141, low expression of CD11b and CD11c, and the lack of CD14 and SIRPα ^[26]^[25]^[40]. It can also be defined by the intracellular detection of IRF8, without IRF4, which represents the standard for identifying this population ^[26]^[25]. Based on many comparative studies of human CD141⁺ DCs with their murine counterpart CD8⁺/CD103⁺ DCs, many other markers have been recognized to allow for a more accurate identification of this specific population. The cell surface expression of the C-type-lectin CLEC9A (also known as DNGR-1) and the presence of the adhesion molecule CADM1 (NECL2) and the protein BTLA (CD272) substantially increase the preciseness of the identification ^[26]^[25]^[39]^[40]. Among Toll-like receptors (TLRs), cDC1 express TLR3 and TLR9, while lacking TLR4, 5, and 7 ^[26]^[25]^[39]^[40]. Additionally, indoleamine 2,3-dioxygenase (IDO) is also highly expressed in this DC subset ^[26]^[25]. Between these receptors, human CD141⁺ DCs can also be characterized by the expression of the chemokine receptor XCR1 ^[26]^[25]^[33]^[40]^[41].

Following the commitment to the cDC1 pathway, the heterogeneity of CLEC9A⁺ CADM1⁺ CD141⁺ lineage in the blood was also reported, splitting this population between XCR1⁻ CXCR4^hi and XCR1⁺ DCs ^[38]. After in vitro culture of the XCR1⁻ cells, this DC subset proliferated and acquired XCR1 expression, indicating that these cells are immediate precursors of XCR1⁺ cDC1 ^[38]. Similarly to mice splenic cDC1, this might indicate the existence of a two-staged differentiation process of human CD141⁺ DCs: a pre-cross-presentation phase and a subsequent cross-presenting stage, in which cDC1 acquire the capacity to cross-present antigens due to the GM-CSF-mediated expression of XCR1 (Figure 1) ^[38]^[31].

3. The Role of cDC1 in Immunity

In light of the current knowledge on DC immunobiology, cDC1 (CD141^hi CLEC9A⁺ XCR1⁺) are the most effective human cross-presenting cells and thus potent CTL inducers ^[26]^[25]^[42]. These functional traits are empowered by the expression of molecules such as CLEC9A and XCR1. CLEC9A is a receptor for actin filaments exposed by necrotic cells, allowing their recognition, internalization and routing into the cross-presentation pathway ^[26]^[25]^[43]^[44]^[45]. In turn, XCR1 is the receptor of the X-C motif chemokine ligand 1 (XCL1) and is restrictively expressed by human CD141⁺ DCs ^[42]. XCL1, also known as lymphotactin, is selectively expressed in NK and CD8⁺ T cells at a steady-state, being enhanced during infectious and inflammatory responses ^[46]. Therefore, the XCL1-XCR1 axis promotes the physical engagement of NK and CD8⁺ T cells with CD141⁺XCR1⁺ DCs, which amplifies their activation state ^[26]^[25]^[33]^[42]^[47]. In mice, CD8⁺ T lymphocytes abundantly secrete XCL1 after in vivo antigen recognition through CD8⁺ DC presentation, increasing the number of antigen-specific CD8⁺ T cells and their capacity to secrete IFN-γ. In contrast, the absence of XCL1 was shown to impair cytotoxic responses to antigens cross-presented by CD8⁺ DCs ^[48]. Finally, the XCL1-XCR1 axis also plays a role in immune homeostasis, specifically in the intestine, where XCL1 produced by activated T cells attracts and enables XCR1⁺ DC maturation, which in turn provides support for T cell survival and functioning ^[49].

CD141⁺ XCR1⁺ DCs have been shown to be required for CD8⁺ T cell responses upon viral and bacterial infections ^[41]. During viral infections, pDCs accumulate at sites of CD8⁺ T cell activation, leading to the production of XCL1 by these activated T cells, which in turn attracts CD141⁺XCR1⁺ DCs. This interaction of pDCs, CD141⁺XCR1⁺ DCs and CD8⁺ T cells leads to optimal signal exchange, where type 1 interferons (IFN1) produced by pDCs improve the maturation and cross-presentation by CD141⁺XCR1⁺ DCs, thus enhancing the development of the CD8⁺ T cell response ^[50]. In the case of secondary infections, CD141⁺XCR1⁺ DCs are needed for the optimum expansion of memory CTLs in response to most pathogens. Moreover, the reactivation of memory CTLs relies on their interactions with CD141+XCR1⁺ DCs, an event that is triggered by the DC production of IL-12 and CXCL9 in response to NK cell-derived IFN-γ ^[51].

The relevance of cDC1 subsets in tumor immune surveillance has not yet been fully established; however, collected data from experiments with cDC1-deficient animal models, such as Batf3–/– mice, have revealed that these cells may play a central role ^[52]. In fact, the above-mentioned models fail to spontaneously reject tumor grafts and are unable to support adoptive T cell therapies or to adequately respond to an immune checkpoint blockade ^[53]^[54]^[55]^[56]. Additionally, studies specifically addressing the nature of DC subsets responsible for cross-presenting peripheral tumor antigens have evidenced migratory XCR1⁺ DC as responsible for priming CTL responses ^[57]^[58].

Although cDC1 are a scarce immune population in the tumor microenvironment, their abundance positively correlates with patient survival across several cancers and is an indicator of the responsiveness to therapy with immune checkpoint inhibitors ^[54]^[55]^[56]^[59]. A larger number of cDC1 were detected in sentinel lymph nodes of patients with melanoma that received combined low-dose CpG-B and GM-CSF treatment. In vivo and in vitro studies showed that these DCs were derived from blood CD141⁺ cDC1 precursors that were recruited to the sentinel lymph nodes by type I IFN and afterward maturated under the combined effect of CpG and GM-CSF. The presence of in vivo CpG/GM-CSF-induced CD141⁺DCs in sentinel lymph nodes was correlated with an increased cross-presenting capacity, T cell infiltration and patient survival ^[60]. Concordantly, it has been shown that regressing human tumors have higher numbers of intratumoral cDC1, which are necessary for efficient CTL-mediated tumor elimination ^[54].

In addition to the cross-presentation of tumor antigens to naïve CD8⁺ T cells predominantly occurring in tumor-draining lymph nodes, cDC1 also play an important role in orchestrating local anti-tumor immunity ^[61]. In the tumor microenvironment, cDC1s are the main source of CXCL9 and CXCL10 chemokines, which are chemoattractants for CXCR3⁺ effector cells, such as T cells, NK cells and innate lymphoid cells (ILC1) (Figure 2) ^[62]^[63]^[64]. By locally producing high amounts of IL-12, cDC1 help to sustain CTL cytotoxicity and INF-γ production by NK cells ^[65]^[66]. In turn, IFN-γ enhances IL-12 production by cDC1 and potentiates antigen cross-presentation ^[67]^[68]. This crosstalk assumes a higher complexity level since NK and CD8⁺ T cells produce several factors that promote the recruitment, retention and local expansion of cDC1. In addition to XCL1, NK cells produce CCL5, with mRNA levels of these two chemokines being closely correlated with gene signatures of both NK cells and cDC1 in human biopsies, and associated with overall patient survival ^[69]^[70]. This suggests that both chemokines may play an important role in attracting cDC1 from blood or surrounding tissues into tumors. Finally, NK cells were recently shown to be one of the major sources of intratumoral Flt3L. This growth factor sustains the viability and functional capacities of cDC1 within the tumor microenvironment and promotes their local differentiation from recruited precursors ^[71]. Although most chemokines secreted by tumor cells are chemoattractants of pro-tumorigenic immune cells, such as macrophages and Tregs, in certain circumstances, the production of CCL3, CCL4 and CCL5 mediates the recruitment of cDC1. In accordance with this, the activation of WNT/β-catenin in melanoma cells was shown to result in the ATF3-dependent repression of CCL4 transcription that in turn was correlated with decreased cDC1 numbers at the tumor site ^[72].

Figure 2. cDC1 interplay with CD8+ T and NK cells to develop anti-tumor responses. NK and CD8⁺ T cells express XCL1, which attracts XCR1⁺ cDC1 into the tumor microenvironment. In addition, NK cells can also produce CCL5, helping to recruit this subset of DCs. In turn, cDC1 are the main source of the chemokines CXCL9 and CXCL10, chemoattractants for T and NK cells. Functionally, cDC1 are highly capable of cross-presenting tumor antigens via MHC-I to CD8⁺ T cells and producing IL-12, which promotes T cell cytotoxicity and the production of INF-γ by NK cells. Furthermore, NK cells produce Flt3L that holds up the viability and functional capacities of cDC1 within the tumor microenvironment and can also promote their local differentiation from recruited precursors. cDC1, classical dendritic cell 1; Flt3L, FMS-like tyrosine kinase 3 ligand; IFN-γ, interferon gamma; MHC-I, major histocompatibility complex I; NK, natural killer; TCR, T cell receptor; XCL1, X-C Motif Chemokine Ligand 1.

4. Exploiting cDC1 in Cancer Immunotherapy

Given the functional specificities of cDC1, strategies aimed at their mobilization to the tumor microenvironment, as well as their expansion and activation, are viewed as highly promising approaches for boosting anti-tumor immunity and improving the success of cancer immunotherapies (Table 1). However, the fragility and scarcity of CD141⁺XCR1⁺ DCs in peripheral blood has hindered their broader study and clinical exploitation. CD141⁺ DCs represent only ~0.03% of human PBMCs, meaning that their isolation would not result in a sufficient quantity for their use as a therapeutic vaccine ^[39]. Furthermore, while there are already approved clinical-grade reagents for the isolation of pDCs and cDC2, equivalent reagents are still lacking for the specific extraction of CD141⁺ DC populations. For these reasons, anti-tumor vaccines based on naturally circulating pDCs and cDC2 have already been directly assayed in several clinical trials with encouraging results (NCT01690377, NCT02993315 and NCT02692976), while there has been no registered trial for cDC1 until the present (February 2020) ^[73]^[74]^[75]^[76]^[77].

Table 1. Overview of existing approaches aiming to explore cDC1s for anti-tumor immunotherapies.

Approach	Studied Species	Cell Subset	Differentiation Cocktail	Antigen Type	Target/Tumor Model	Combination Therapy	Ref
ex vivo differentiation	Human	CD34⁺-derived CD141⁺ CLEC9A⁺ DCs	SCF, GM-CSF, IL-4 and Flt3L	-	-	-	^[21]^[38]^[37]^[78]
	Human	CD34⁺-derived cDC1	Flt3L, SCF, TPO, IL-6 and StemRegenin1	-	-	-	^[79]
	Human	Monocyte-derived CD141⁺ XCR1⁺ DCs ¹	GM-CSF and IL-4	-	-	-	^[80]
	Human	CD141⁺ XCR1⁺ DCs	MA and LAM	-	-	-	^[81]
	Human	iPSC-derived CD141⁺ XCR1⁺ DCs	GM-CSF, SCF, VEGF and BMP4	Melan A	²		^[82]
	Human and murine	Fibroblast-derived cDC1	PU.1, IRF8 and BATF3	-	-	-	^[36]
Naturally occurring cDC1	Murine	Natural cDC1	-	UV-irradiated tumor cell lysates	B16 melanoma MC38 colon adenocarcinoma	Anti-PD-1	^[83]
Naturally occurring cDC1	Murine	Tumor-derived cDC1	-		B16 melanoma LLC lung carcinoma		^[84]
mAb- or XCL1-based direct in vivo targeting	Murine	CD8α⁺ DC	-	IgG2a mAb Ovalbumin	-	-	^[85]
	Murine ³	XCR1⁺ DC	-	Ovalbumin	EL4 thymoma	-	^[86]
	Murine	CD8α⁺ DC	-	Ovalbumin	P3X63Ag8.653 myeloma	-	^[87]
	Murine	CD8α⁺ DC	-	Ovalbumin	B16 melanoma	-	^[88]^[89]
	Murine	CD8α⁺ DC	-	Ovalbumin	B16 melanoma and lung pseudometastases	-	^[90]
	Murine	CD8α⁺ DC	-	MUC1	MC38 colon adenocarcinoma	-	^[91]
	Murine	CD8α⁺ DC	-	Nanoemulsion Ovalbumine	PyMT-mChOVA breast cancer and lung metastases B16 melanoma HPV-related TC1 cancer	-	^[92]
	Human ⁴	Allogeneic neuroblastoma cells	-	-	Neuroblastoma	-	NCT01713439 NCT00703222 ^[93]
	Human ⁴	Autologous neuroblastoma cells	-	-	Neuroblastoma	-	NCT00062855 ^[94]
	Human ⁴	Allogeneic neuroblastoma cells	-	-	Neuroblastoma	Cytoxan	NCT01192555
WH-based direct in vivo targeting	Murine	CD8α⁺ DC	-	Ovalbumin	B16 melanoma	-	^[95]
Indirect in vivo targeting	Murine	IFN- α -iPSC-pMCs			B16 melanoma EL4 thymoma MC38 colon adenocarcinoma CT26 colorectal adenocarcinoma 4T1 breast cancer	Anti-PD-1/anti-PD-L1	^[96]
Indirect in vivo targeting	Murine	CD8α⁺ DC	-	Allogeneic T cells	-	-	^[97]

¹ Adherent fraction; ² Functionality assays; ³ Transgenic mice expressing human XCR1; ⁴ Clinical trial.

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