Infiltration of immune cells in solid tumor: a strong prognostic marker .

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Suppression by metabolic disruption

There are several mechanisms discovered which are referred to as mechanisms that mediate `metabolic disruption’ of the effector T cell target. One of these mechanisms suggested is high expression of CD25 on the surface of Tregs. This enables Tregs to `consume’ local IL-2 and therefore starve actively dividing effector T cells by their survival (Thornton, Shevach 1998). Another mechanism includes the intracellular or extracellular release of adenosine nucleotides. Molecules like CD39 and CD73 concordantly expressed on the surface of Tregs for adenosine generation. This suppresses the effector T cell function through activation of the adenosine receptor 2A (A2AR) (Deaglio et al. 2007). Tregs also suppress the effector T cell function directly by transferring the potent inhibitory cAMP into effector T cells (Bopp et al. 2007).

Cell to cell contact dependent suppression: Involvement of co-stimulatory and co-inhibitory signals

The antigen recognition by T cells is initiated through the TCR engagement but its amplitude is regulated by the balance between the co-stimulatory and inhibitory signal strength (these co-stimulatory and inhibitory molecules known as ICPs) (Zou, Chen 2008). In normal physiological conditions, the expression of these ICPs (ICP) maintains the self-tolerance and prevents the host from autoimmunity in case of pathogenic infections, but tumor cells can deregulate expression of the ICP by immune cells through various mechanisms. One of the mechanisms includes the recruitment of Tregs and their activation in tumor microenvironment via interaction of tumor cells or immune cells and Tregs through the ICPs expression.
Along with cytokines expressed in the environment, Tregs also suppress the T cells and DCs by expression of ICP molecules on their surface. With the help of in vitro suppression assay, many molecules are discovered participating in cell to cell contact-dependent suppression.
One of the important negative regulator molecules among this is CTLA-4 (CD152). CTLA-4 is co-expressed with CD28 on the TCR engagement by T cells. CD28 and CTLA-4 share common ligands i.e. CD80 and CD86 (on APC) and it have been proposed that the CTLA-4 with stronger affinity to these ligands out-compete the CD28 interaction and thus induce inhibitory signal to T cells. Tregs in thymus and periphery constitutively express CTLA-4 whereas upon activation naïve Tregs may express CTLA-4 (Miyara, Sakaguchi 2007).Expression of CTLA-4 on peripheral Tregs is associated with the rapid homeostasis, and inhibition by soluble CTLA-4 (CTLA-4 Ig) leads to the decrease in the numbers of the Tregs and CTLA-4 expression in vivo(Tang et al. 2008). Blockade of CTLA-4 by Fab fragments of anti-CTLA-4 monoclonal antibody and experiment in CTLA-4 deficient mice shows abrogation of CD4+CD25+Treg-mediated suppression (Sakaguchi S. 2004,(Read et al. 2006). It has been suggested that Tregs might interact with CD80 and CD86 molecules on APC via CTLA-4 and transduce a co-stimulatory signal to Tregs i.e. signals via both CTLA-4 and TCR might interact and activate Tregs to exert suppression (Wing et al. 2008). Another possible role of CTLA-4 for Treg function is that it might trigger induction of the enzyme IDO in DC by interacting with their CD80 and CD86 (Onodera et al. 2009). Anti-CTLA-4 blockade on both effector cells as well as Tregs is found to be effective to improve the anti-tumor activity in melanoma (Peggs et al. 2009). It has been found that along with the suppression of the effector function and proliferation of the CD8+ T cells, Tregs participate in the effector to memory transition of CD8+ T cells through CTLA-4 signaling during LCMV viral infection in mice (Kalia et al. 2015).
Ivars and colleagues first reported that Tregs could down regulate the expression of co-stimulatory molecules CD80 and CD86 by DC in vitro(Lukas Cederbom, Håkan Hall and Fredrik Ivars 2000). Moreover, studies show that, LAG-3 may block DC maturation. Binding of LAG-3 to MHC-II molecules (Liang et al. 2008)expressed by immature DC induces an immunoreceptor tyrosine-based inhibition motif (ITIM)-mediated inhibitory signaling pathway which involves FCγR and extracellular signal regulated kinase (ERK)-mediated recruitment of SHP-1 that suppresses DC maturation and their immunostimulatory capacity (Vignali, Dario A A et al. 2008). Tregs from LAG3-/- mice showed reduced immunosuppression (Huang et al. 2004). Along with LAG-3, a molecule Neurophilin-1 promotes prolonged interactions with Tregs and immature DC (Sarris et al. 2008).

How many mechanisms do Tregs need? Treg plasticity

Presence of Tregs in the pathogenic and inflammatory conditions and its positive or negative consequences depends on the phenotypic and functional status of Tregs in these situations. Since Tregs are flexible with the expression of repertoire of the molecules shared with the other CD4+ T cells; it reflects their functional potential in vivo. Considerable research has been carried over the past few decades in understanding the molecular basis underlying the immune regulation by Tregs. But still the questions remains that how many mechanisms are involved at the same time in the tolerance mediated by Tregs? Consequences of autoimmunity arise due to disruption of any one or more than one immunosuppression mechanism(s)?
This suggests that either key mechanisms of immunosuppression have yet to be identified or multiple mechanisms work in the concert to mediate Treg function. It is observed that in absence of IL-10/IL-35, the Tregs are still functional in vitro and in vivo and express cathepsin E (CTSE) which is required for expression or release of TNFR member TRAIL, mediating apoptosis (Pillai et al. 2011). This suggests that loss of certain regulatory mechanisms may result into forced molecular changes that are compensated by “switch on” inhibitory mechanisms. Secondly, it also suggests the existence of cross regulatory pathways which may operate in utilization of certain immunosuppression mechanisms. Collectively, it may serve to facilitate Treg plasticity (Sawant, Vignali, Dario A A 2014).

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Antigen specificity of Tregs in cancer

Tregs have an important immuno-pathological role in human cancer by lowering the TAA-specific T cell immunity contributing to tumor growth. First target antigen of Tregs to be reported in human was LAGE-1, a family member of NY-ESO-1. It was described as a candidate for direct recognition by Tregs from clones derived from TILs of melanoma patients (Wang et al. 2004). Targets of Tregs are generally believed to be self-antigens which may require to be expressed in the thymus. Tumor antigens are mostly aberrantly expressed by normal cells or so called oncofetal antigens which are self-antigens that are normally expressed in epithelial cells as well; it is likely that small part of Tregs generated in the thymus is specific for these tumor-associated antigens. Tregs specific for self-antigens LAGE-1 and ARTC-1 are present among melanoma-infiltrating lymphocytes. These Tregs have a phenotype similar to thymus-derived Tregs in terms of FoxP3, GITR, CTLA-4 and CD25 expression and cytokine production (Wang et al. 2004; Wang et al. 2005).
Most recently, Tregs specific for melanoma antigen gp100, TRP-1, NY-ESO-1 and Surviving were revealed in peripheral blood of melanoma patients (Vence et al. 2007). Although it is likely that the Tregs are educated in the thymus, the Tregs generated in periphery cannot be excluded. The nature of tumor-specific antigens (TSA) dictates that TSA-specific Tregs must be induced in periphery.

Table of contents :

Index of figures
Index of tables
A. Introduction
1. Immune system and tumors: a complex discourse
1.1. Origin of the concept of tumor microenvironment
1.2. Origin and concept of immune surveillance
1.2.1. Immunoediting: 3 `E’ concept
1.3. Tumor microenvironment: a complex interactome
1.3.1. Characteristics of contexture
1.3.2. Cancer associated TLS General characteristics of TLS Formation of TLS
1.3.3. TLS in anti-tumor immune response
1.4. Infiltration of immune cells in solid tumor: a strong prognostic marker ..
1.4.1. Prognostic importance of the TLS in cancer
2. Tregs: Key Regulators of anti-tumor immune response
2.1. Discovery and features of regulatory T cells
2.2. Regulatory T cell subsets
2.3. Regulatory mechanisms exerted by Tregs
2.3.1. Inhibitory cytokines
2.3.2. Suppression by cytolysis
2.3.3. Suppression by metabolic disruption
2.3.4. Cell to cell contact dependent suppression: Involvement of co-stimulatory and co-inhibitory signals
2.4. How many mechanisms do Tregs need? Treg plasticity
2.5. Infiltration, differentiation and activation of Tregs in tumor microenvironment
2.5.1. Infiltration of Tregs in tumor microenvironment
2.5.2. Expansion and activation of Tregs
2.5.3. Antigen specificity of Tregs in cancer
2.6. Tregs in cancer: ambiguity in prognostic importance
3. Tregs and immunotherapy: a blessing in disguise?
4. Lung cancer: a study model
4.1. Etiology and histology of the lung cancer
4.2. TNM classification and survival of patients
4.3. Treatment of lung cancer patients
4.4. Era of combined therapies: promising for NSCLC
B. Hypothesis and objectives
C. Results 
Tregs in advanced stage chemotherapy treated lung cancer patients
D. Discussion
TLS in lung tumors: centers of the protective immune responses
Infiltration, activation of Tregs in cancer microenvironment
Anti-inflammatory role of Tregs in lung cancer
Tregs in TLS: Proponents or opponents?
Expansion of the specific subsets of Tregs in TLS
Modulation of the Treg phenotype in the neoadjuvant chemotherapy treated lung cancer
Prognostic outcome of Tregs in lung cancer patients
E. Limitations of this study
F. Conclusion and perspectives
G. References
Publication bibliography
H. Annex 


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