Efficiency and the ultimate success of such a communication hinges upon the maturation status of the DCs, attained following their interaction with cancer cells. Immature DCs facilitate tolerance toward cancer cells observed for many apoptotic inducers while fully mature DCs can strongly promote anticancer immunity if they secrete the correct combinations of cytokines [observed when DCs interact with cancer Mature no 438 undergoing immunogenic cell death ICD ].
However, an intermediate population of DC maturation, called semi-mature DCs exists, which can potentiate either tolerogenicity or pro-tumorigenic responses as happens in the case of certain chemotherapeutics and agents exerting ambivalent immune reactions.
In the present review, we discuss these different maturation states of DCs, how they might be attained and which anticancer agents or cell death modalities e. ICD may these states.
It is conceptually established that the immune system can be distributed across two basic components, i. Together these two branches of the immune system are supposed to initiate acute inflammation ultimately culminating in its resolution and wound healing once they have taken care of the aggressor, insult, or diseased cell 56.
It is noteworthy that Mature no 438 terms of evolution, the conception of the innate immune system pre-dates that of the adaptive immune system 1. Most notable innate immune cells include macrophages, natural killer NK cells, dendritic cells DCsvarious myeloid lineage subsets, neutrophils, basophils, and eosinophils 16 ; while the most notable adaptive immune cells include T and B lymphocytes 3 Mature no 438, 5.
This adaptive immune cell priming helps to initiate more specific responses, directed against the acquired antigens and leading to the eradication of the antigen source 36. This leads to both: While most innate immune cells professional presenters and certain cells of epithelial lineage non-professional presenters are capable of presenting antigens to the adaptive immune cells 6 be it to varying degrees; yet the sentinel antigen-presenting cells APCs of the immune system are DCs 239.
In the present review we briefly discuss the basic biology of DC activation states that can make a difference between pro-tumorigenic inflammation and anti-tumorigenic immunity. We will then discuss in more detail the ability Mature no 438 anticancer therapeutics to influence and modulate these activation states and the crucial impact of exosomal communication on Mature no 438 functions. The molecular cell biology of DCs has evolved in a sophisticated manner to facilitate its APC functions Dendritic cells are also special in terms of their antigen processing machinery.
Classically for non-professional APCs and normal cells, as applicable Mature no 438, antigens derived from intracellular sources are presented by the major histocompatibility complex MHC class I presentation system while extracellular antigens captured via phagocytosis or pinocytosis are preferentially processed for MHC class II presentation Depending on the environment they encounter e.
Based on a highly stark difference between antigenic environments, i. The distinction between immature and mature DCs is partly based on changes occurring on two crucial levels, i. DCs stimulated on the functional level exhibit the ability to secrete cytokines where the balance between inflammatory or immunostimulatory cytokines e.
DCs provide the T cells with the information about whether an antigen is present and whether it poses a threat — a foundational mechanism for the subsequent T cell effector function However in this case the T cells are not polarized toward Mature no 438 effector state but are rather polarized to facilitate tolerance or immunosuppression 12 Such immunotolerance is actively induced and maintained through a mixture of immune checkpoint pathways and complete lack of stimulatory signals provided by the DCs Such immunosuppressive T cells e.
On the other hand, when DCs encounter pathogens or entities possessing PAMPs detected in part through PRRs they switch to a mature state exhibiting strong Mature no 438 and functional stimulation. At this stage, the DCs leave the function of phagocytic scavenging and assume the more sophisticated APC-function Subsequently, DCs carefully co-ordinate their proteolytic processes in the cytosol e.
These ligands help in providing proper co-stimulation by binding corresponding receptors on T cells signal 2, detected by T cell receptors like CD28, CD40L in the presence of cytokines or factors immunostimulation and the effector T cell phenotype signal 3, detected by "Mature no 438" cytokine cognate receptors 9.
The presence of these three signals is absolutely essential for effective T cell stimulation by APCs like DCs and their polarization toward anti-pathogenic effector function 69. It is noteworthy though, that apart from these three signals, DCs might modulate T cell function via other immunomodulatory signals e.
Pre-existing cytotoxic T cells and memory T cell populations are not very strongly dependent on fully mature DCs for their effector functions 23 The continuum of DC activation states is Mature no 438 more complex when it comes to cancer as most cancerous tissues or tumors are very similar in terms of antigenic make-up to that of normal cells 5 This is attributable to the fact that most antigens are either shared with nearby normal tissues e.
This situation is further exacerbated by the capacity of cancer cells to interfere with normal DC function 23 via immunosuppressive cytokines or other signals like those conveyed by exosomes discussed later. Such immature TIDCs tend to exhibit dysfunction in antigen-presenting capabilities, suppressed endocytic activity, abnormal motility, and various other immature characteristics — a point that has been demonstrated in a number of studies analyzing various solid tumors and tumor-draining lymph nodes Moreover, tumors may also actively induce apoptosis in TIDCs through certain gangliosides e.
Mature no 438 representation of different states of DCs interacting with different types of cancer cells. Live cancer cells and cancer cells undergoing non-immunogenic cell death keep the steady state DCs in an immature state devoid of strong up-regulation of phenotypic maturation ligands CD80, CD86, CD83, MHC-II and functional maturation no or negligible amounts of immunostimulatory cytokines.
Both immature DCs and semi-mature DCs cause T cell anergy and facilitate tolerogenicity thereby compromising anticancer immunity. These DCs may also actively facilitate pro-tumorigenic signaling.
However, some therapeutic paradigms can induce immunogenic cell death ICD or at least a certain level of augmented immunogenicity in cancer cells which causes the interacting DCs to fully mature.
These fully mature DCs can Mature no 438 elicit anticancer immunity. Fully mature DCs devoid of immunosuppressive cytokines like IL can be termed as immunogenic DCs capable of forming the most productive interface with T cells to prime them for anticancer effector function.
The role of Th17 cells in cancer immunity and progression is enigmatic and controversial. The tumor-induced iDCs state is Mature no 438 characterized by: Such iDCs can also be encouraged by the presence of non-immunogenic cancer cell death [e.
The "Mature no 438" of signal 1, i. Thus not surprisingly, one of the immunoevasive strategies employed by cancer cells is the down-regulation or loss of antigens 7 T cells integrate antigenic stimulus from several such Phase I encounters until the cumulative signal triggers the onset of Phase II.
Thus, lower cancer cell-associated antigen levels make it harder for the T cells to exit Phase I — a scenario that leads to unstable DC—T cell interactions and compromised T cell immunity.
Such studies need to be extended to settings of DC—T cell interactions within a tumor-bearing host, in near future. The strategies and mechanisms employed by cancer cells for inducing DC-based tolerogenicity have been discussed in details in certain recent reviews 5 — 7 Curiously it has been demonstrated recurrently that in an ex vivo set-up, certain iDCs may exhibit the ability Mature no 438 directly lyse transformed cells or tumor cells in vitro While, IKDCs may simply reflect the prevalent ex vivo DC heterogeneity yet their characterization raises the need to better study DC features in tumor-bearing hosts.
As per the theory of cancer immunoediting, during tumor development the equilibrium between growing tumor and immune system shifts: It has been long proposed that anticancer therapies should kill the cancer cells in a Mature no 438 that helps activate the DCs to prime adaptive immune system for activity 2835however the experimental as well as clinical translation of this idea have unfortunately not been straightforward.
For instance, certain therapeutic modalities e. It is noteworthy though that in certain instances, semi-mature DCs generated ex vivo and injected back into the host in this case rhesus macaque might become mature spontaneously during migration before reaching the lymph nodes However, whether this situation applies to therapeutic DC vaccines is an enigmatic question since the above mentioned study was not done within the context of anticancer DC vaccines.
Thus, semi-mature DCs, unlike iDCs, exhibit the ability to sustain at least two i. It is also noteworthy that certain well-established tumors composed of immunogenic cancer cells e. Together iDCs and semi-mature DCs tend to encourage T cell anergy or T cell exhaustion 910tolerogenicity toward the cancer cell 931and even active pro-tumorigenic activity e.
Inducers of cancer cell death that stimulates full maturation of DCs. Recently however, it was described that certain therapeutic modalities [e. ICD tends to be highly immunostimulatory because it emits a spatiotemporally defined combination of potent DAMPs that act as danger signals important for DCs stimulation DCs detect such danger signals through a combination of receptors including TLRs, CD91, and purinergic receptors 21 ICD may also ablate the canonical strategies harnessed by cancer cells to encourage the formation of immature or semi-mature DC states 21 Beyond ICD, some anticancer therapeutics e.
In general, fully mature DCs exhibit all three conventional T cell stimulatory signals, thereby enabling elicitation of potent anticancer immunity 1213 However, based Mature no 438 the pattern of only a few cytokines fully mature DCs might be subdivided, i. The fully mature immunogenic DCs are supposed to exhibit the least or total absence of immunosuppressive cytokines like IL 1721 Most known ICD inducers result in the formation of general fully mature DCs, with a context-dependent absence or reduced abundance of immunosuppressive cytokines e.
On the other hand, the presence of high IL cytokine expression might be a marker of inflammatory DCs It is noteworthy that Mature no 438 role of inflammatory DC-Th17 arc in cancer progression is still enigmatic with evidence supporting both anti-tumorigenic and pro-tumorigenic roles for this interaction, depending on the context 4446 Thus for anticancer immunity, the functional role of fully mature inflammatory DCs needs to be treated with caution until further research ascertains their exact behavior.
It is noteworthy though, that the distinctions between different DC maturation or activation states made on the basis of phenotypic maturation markers or cytokine patterns are primarily based on ex vivo or in vitro experiments. This is because simultaneous analysis of various surface-associated and soluble DC activation markers is relatively easy ex vivo or in vitro.
However, in vivo or Mature no 438 situsuch a simultaneous detection is nearly impossible. In vivo or in situmostly only the phenotypic maturation status of tumor-infiltrating DCs is detected via immunofluorescence staining e. While an analysis of cytokines associated with the tumor is possible via RT-PCR, proteomics-approaches, or "Mature no 438" arrays, yet there is no way of characterizing which cytokines are secreted exclusively by the TIDCs.
Anticancer therapies are capable of modulating DC states, either directly or via dying cancer cells.