Immune system and tumors: a complex discourse

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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).
Programmed cell death -1 (PD-1; gene pdcd1) a molecule of immunoglobulin superfamily has been found a second promising molecule after CTLA-4 implicated in the immunotherapy for cancer patients. A CD28 family molecule and is expressed by activated T cells, B cells and NK cells. It binds to the ligands PD-L1 (CD274) and PD-L2 (CD273). PD-1 and PD-L1 interaction leads to the blocking of the stop signal after TCR ligation and thus promotes the tolerance (Fife et al. 2009). CTLA-4 blocks the activation of T cells whereas the PD-1 blocks the effector T cell functions in tumors and inflammatory tissues. PD-1 induces the cell death of antigen specific T cells and thus leading to the prevention of autoimmunity simultaneously reducing the apoptosis on the Tregs. PD-L1 expression by the cancer cells leads to the increase in the apoptosis of the effector T cells and thus thought to be an evasion mechanism manifested by the tumors to escape the immune responses (Chen et al 2002).PD-1 pathway blockade led to the reversal of exhaustion of the CD8+ T cells in LCMV infection (Barber et al. 2006).PD-L1 has showed important role in the Tregs development. PDL1-/-antigen presenting cells minimally induced the conversion of CD4+ T cells in iTregs. PD-L1 enhances the expression of the FoxP3 and suppression potential via down regulation of phosphorylation of Akt, mTOR and ERK2 and up-regulation of the PTEN which are key signaling molecules in the development of Tregs (Francisco et al. 2009).
Several co-stimulatory and co-inhibitory molecules are involved in the regulation of the T cell and APC interaction after the first TCR MHC interactions deliver the activating signal to the T cells. + In green circle represents the positive signal to the T cell or APC whereas – in red circle represents the negative signal to T cells Like PD-1, Tim-3 has been found as negative regulator molecule and is expressed on CD4+ and CD8+ T cells in infection and tumor. Interaction of Tim-3 on Tregs and Tim-3L on the Th1 cells (Wang et al. 2009) leads to the tolerance of auto and allo-immune responses in diabetes mice model (Sánchez-Fueyo et al. 2003). Expression of Tim-3 on activated CD4+ T cells lead to the negative regulation of cytokine production by Th1 and Th17 cells (Hastings et al. 2009). It has been found that Tim-3 expression on the CD4+ TIL in lung cancer is associated with the worst pathological parameters (Gao et al. 2012).
A recently immerging molecule TIGIT (expressed by T and NK cells) has been found to play important role in immune-regulation. The TIGIT/CD226 pathway has been discovered to be operational between the Tregs and DCs. This pathway acts similarly the CD28/CTLA-4 co-stimulatory pathway (Joller et al. 2011). TIGIT (T cell Ig and ITIM domain) is a trans-membrane glycoprotein which can bind with high affinity receptor CD155 on monocytes and CD11c+ human DC. TIGIT and CD226 share a common receptor CD155 and thus have a competition for the binding. It has been observed that TIGIT engagement with CD155 on DC leads to the IL-10 production by DC and diminished production of IL-12p40 (Yu et al. 2009). Ligation of TIGIT on Tregs induced the expression of fibrinogen- like protein 2 (Fgl2) (a molecule involved in the cytokine production by Th2) and inhibited pro-inflammatory responses by Th1 and Th17 (Joller et al. 2014). It is also observed now that Helios+ memory Tregs expressing TIGIT and FCRL3 are highly suppressive Tregs (Bin Dhuban et al. 2015; Fuhrman et al. 2015).
ICOS (CD278) is another CD28 super family member which enhances T cell responses to foreign antigen. ICOS was found to be expressed by the T cells which are closely associated with B cells in germinal centers (Hutloff et al. 1999). ICOS expression is considered to be important in CD4+ T cells for Th1 or Th2 polarization but not involved in CTL responses in viral infections (Kopf et al. 2000). Intermediate ICOS expression on the CD4+ T cells is associated with pro-inflammatory Th2 cytokines like IL-4, IL-5 and IL-13 whereas, ICOShigh T cells are associated with the anti-inflammatory cytokine IL-10 (Lohning et al. 2003). ICOS-L expression by melanoma cells found to promote the activation of Tregs (Martin-Orozco et al. 2010). In tumor microenvironment, ICOS-L expression by plasmocytoid DCs results into infiltration of Tregs and leads to immunosuppression (Faget et al. 2012b; Conrad et al. 2012).
Presence of TNF-α during the pathological consequences leads to the expression of TNF superfamily receptors on T cells especially Tregs. Neonatal administration of the anti-TNF-α increased the Tregs in NOD mice (McDevitt et al. 2002). In memory Tregs (CD45ra-) TNF-a induces NF-kB pathway in the Tregs but not in CD25- conventional T cells and leads to the expression of FAS, TNFR-2, 4-1BB and OX-40 on Tregs, which decreases their suppressive potential but the effect was reversed when the anti-TNFR2 mAB treatment was carried out during the in vitro cultures of T cells (Nagar et al. 2010). But contradictory studies also show that TNFR2 expression augments the Treg activity in ovarian cancer (Govindaraj et al. 2013) and their function in inflammatory responses (Hamano et al. 2011; Chen et al. 2013). Co-expression of GITR, OX-40 and TNFR2 along with TCR signaling has been found to favor the thymic differentiation of Tregs (Mahmud et al. 2014).
CD40-CD40L interaction helps primary CD8+ T cell responses via several mechanisms. Engagement of CD4+ T cells to DC via CD40-CD40L licenses antigen presentation potential to DC for activation of the CD8+ T cells (Bennett et al. 1998). Memory T cell generation is dependent on the CD40 and ligand interaction (Bachmann et al. 2004; Shugart et al. 2013).CD40L has been found to be an important molecule in CD8+ T cells, involved in the overcoming Tregs mediated tolerance during the viral infections (Ballesteros-Tato et al. 2013), and tumorigenesis (Soong et al. 2014) and thus, has been considered as promising tool in immunotherapy.
OX-40 is another co-stimulatory molecule involved in the maintenance of the long-term memory T cells. It was found that OX-40-/- T cells produced less IL-2 and Bcl-2 and undergoes apoptosis after 2-4 days of activation. Thus, OX-40 was considered as important signal, as CD28 in T cells (Rogers et al. 2001). OX-40L deficient DCs are found to be defective in inducing co-stimulatory signal to T cells (Chen et al. 1999).OX-40-induced Survivin plays important role in clonal expansion of T cells (Song et al. 2005). Surprisingly the expression of OX-40 was found to have opposite effect on the Tregs. It is found that Ox-40 expression on Tregs turns off their ability to suppress T cell proliferation, IFN-γ production (Vu et al. 2007) and facilitates the tumor rejection (Piconese et al. 2008).
Role of 4-1BB (CD137) in Treg immunity is unclear. Tregs express 4-1BB in response to the IL-2 and CD28 (Elpek et al. 2007b). It has been found that signaling via 4-1BB pathway inhibits the suppressive function of Tregs (Choi et al. 2004).
In addition to CTLA-4, GITR is constitutively expressed in Tregs in higher levels than other T cell subsets, although activated T cells also express GITR (McHugh et al. 2002). GITR ligand is expressed on mouse and human mature DC and pDC and it enhances the immunostimulatory function of DC but do not affect the suppressive function of the Tregs(Tuyaerts et al. 2007). GITR-L expression on CD25- T cells at initiation of immune response renders the resistance to immune regulation but, down-regulation of GITR-L by inflammatory stimuli may enhance the susceptibility of T cells to suppressor activity (Stephens et al. 2004).
In summary, Tregs require the co stimulatory molecules after TCR ligation to become fully functional. As, the immunosuppressive ability of Tregs is considered favorable for autoimmunity prevention and their immunosuppression capacity in the tumor microenvironment is considered as a curse, in the same manner, phenomenon of their ICP expression can be also considered as good or bad in different pathological contexts. Expression of the immune-co-stimulatory and regulatory molecules by Tregs in chronic inflammation like tumors has been and is still being studied largely. It should be noted that none of these pathways only affect the Treg function; simultaneously they also promote or attenuate the effector T cell functions. Nevertheless, the discovery of ICP expression on T cells uncovered the vast field of tumor immunology and is proving to be a phenomenal way to treat patients with immunotherapies. The several ICP markers exploited in the immunotherapy trials in cancer patients is discussed further in the “Tregs and immunotherapy: Blessing in disguise?”

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).
In most scenarios, the primary mechanism employed by the Tregs depends on the disease, the target cell type, the local inflammatory environment and anatomical location. It is considered now that Tregs are not terminally differentiated but have the developmental plasticity to differentiate into special subsets with their local milieu for effective control of immune regulation. This notion is synonymous with the observation that FoxP3 encodes the expression of the core Treg suppressor module (increased CD25, CTLA-4 expression) while their adaptability to the changing environment leads to induction of additional suppressive modules (transcriptional factors, miRNA, suppressive pathways) for optional regulation (Wing, Sakaguchi 2012).
It is observed that Tregs undergo differentiation in parallel with effector T cells. This indicates that Tregs exhibit functional specialization in periphery by adapting the transcriptional program of specific effector T cells they suppress (Duhen et al. 2012). The T-bet+ Tregs that potently inhibit Th1 cell responses are dependent on the transcriptional factor STAT-1 and occurred directly in response to IFN-γ produced by effector T cells (Koch et al. 2012). Similar to T-bet, expression of the Th2 differentiation factor, IRF-4 endows Tregs with ability to control Th2 responses (Zheng et al. 2009). The transcription factor GATA-3 is also highly expressed in the Tregs which may help Tregs to suppress Th2 cells (Wohlfert et al. 2011). Similar to Th1 and Th2, Th17 cells are regulated by the Tregs expressing STAT-3 (Hossain, Dewan Md Sakib et al. 2013). Also, co-expression of other Th17 transcription marker like RORγt is also reported in humans (Ayyoub et al. 2009). Expression of TFH transcription factor Bcl-6 in Tregs has been demonstrated to be essential for Tregs control of germinal center responses (Chung et al. 2011a). Thus, variable expression of transcriptional markers defines functionally specialized sub-phenotypes of Tregs that each control distinct immune responses.
Along with transcription factors, several other mediators of the immune regulation like microRNA, chemokine receptors, and cytokines are used by Tregs to compensate for loss of key modules. Additional studies will clearly be required to determine the prevalence of Treg functional plasticity caused by divergent genetic backgrounds and/or altered environmental circumstances (Cretney et al. 2013).

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Infiltration, differentiation and activation of Tregs in tumor microenvironment

Infiltration of Tregs in tumor microenvironment

Migration of Tregs in tumor microenvironment is well documented in the literature. There are several ways by which Tregs can migrate to tumor microenvironment. The CCL17 and CCL22 produced by plasma cells and macrophages attract the T helper and importantly Tregs in the tumor microenvironment. Major sources of CCL17 and CCL22 like tolerogenic DCs, cells and TAM’s can be found in different tumor microenvironments. Expression of CCL17 and CCL22 in tumors is thought to be responsible for the strong influx of Tregs in several tumor models. In CT26 colon carcinoma mouse model, the CCL17 gene therapy leads to the recruitment of Tregs and thus tumor regression (Kanagawa et al. 2007). When CCR4 antagonist was used in tumor bearing mice, the CD44 hi ICOS+ Tregs were targeted with this treatment, while increasing the antigen specific CD8+ T cell accumulation (Pere et al. 2011).
In human tumors also it is observed that Tregs are recruited in tumor microenvironment via CCL17/CCL22 and CCR4 interaction. Expression of the CCR4 and CCR8 allows Tregs to competitively bind the APC over the conventional T cells and thus affect the activation of the conventional T cells and it is found that CCR8 is more restricted to the Tregs (Iellem et al. 2001). Not only CCR7 but the CCR8 and CXCR4 has also been found to be important for trafficking of the Tregs to the tumors(Wang et al. 2012). Blockade of CCL1 by CpG-ODN and anti-CCL1 led to the reduced number of the Tregs and CD8+ T cells mediated rejection of tumors in mice (Hoelzinger et al. 2010). In pancreatic cancer, disruption of the CCR5 mediated infiltration of Tregs leads to reduced growth of tumors in mice(Tan et al. 2009). IL-6 induced CXCR1 was found to be important in IL-8 expressing lung cancers and melanoma (Eikawa et al. 2010).
Expression of ICOSL and OX-40 by pDC is responsible for recruitment of Tregs in melanoma and breast cancer (Faget et al. 2012a; Aspord et al. 2013). IL-27 produced by DCs also seems to be important for recruitment of Tregs in mouse tumor models (Xia et al. 2014).
Along with the immune cells, the molecules expressed by the tumor cells recruit Tregs in tumor microenvironment. It has been found that VEGF and receptors pathway is involved in the recruitment of the Tregs in tumors. CD4+FoxP3+ Tregs express VEGFR2 and produced high levels of TGF-β (Suzuki et al 2010). In CT-26 bearing colon cancer mouse model, anti-VEGF A and Sunitinib (tyrosine kinase receptor inhibitor) treatment remarkably decreased the Tregs in spleen and tumor (Terme et al. 2013).

Expansion and activation of Tregs

In tumor microenvironment, several cues are responsible for the differentiation and activation of Tregs apart from the TCR/CD28 signaling. Besides recruitment via chemotactic gradients, the tumor microenvironment promotes the expansion of nTregs as well as the generation of iTregs in situ due to the abundance of IL-10, TGF- β and adenosine which is produced by both tumor cells and MDSC (Rabinovich et al. 2007). CD40 and IL-4 produced by MDSC also help the recruitment and proliferation of Tregs in tumor microenvironment (Pan et al. 2010). Up-regulation of IDO by APC has been reported to activate Tregs and promote their proliferation (Sharma et al. 2007). Ligation of CD80 and CD86 by CTLA-4 constitutively expressed on Treg increases the functional activity of IDO by DC forming a positively feedback loop.
IL-2 produced by NK cells and T cells in tumor microenvironment seems to be nourishing Tregs and their expansion in tumor microenvironment (Martin et al. 2010). In IL-2-/- or CD25-/- foxp3gfp knock-in allele mice, it was observed that IL-2 signaling was required for maintenance of the expression of genes involved in regulation of cell growth and metabolism (Fontenot et al. 2005a). It is now showed in mice that in SLO, Tregs gain access through expression of CCR7 whereas the CCR7lo Tregs localize in the non-lymphoid tissues and are insensitive to IL-2 blockade and continue signaling through ICOS (Smigiel et al. 2014). Treatment with IL-2 commonly used for melanomas has found to be expanding the ICOS+ Treg expansion (Sim et al. 2014). TGF-β, an autonomous regulator of tumor initiation, progression, immune escape and metastases in epithelial cells has been observed to play a central role for peripheral expansion of Tregs (Yang et al. 2008). Tumor cells capable of producing TGF-β and in addition can modulate MDSC’s and immature DC to become major sources of TGF-β (Huang et al. 2006).

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.
All these examples suggest that tumor-infiltrating Tregs may recognize self as well as foreign proteins expressed by tumor cells. And both of these types render the tumor specific tolerance.

Tregs in cancer: ambiguity in prognostic importance

Although Tregs act as regulators of the harmful inflammatory responses in autoimmune conditions, their role of in cancer is a matter of debate. There are several examples in the literature which demonstrate this ambiguity in predicting clinical outcome of the cancer patients.
Many publications reported that the density of CD4+FoxP3+ T cells is associated with short-term survival of cancer patients, whereas others reported an absence of correlation with clinical outcome. High number of FoxP3+ Tregs is associated with the improved overall survival in follicular lymphoma (Carreras et al. 2006), in ER-breast cancer (West et al. 2013). In case of Head and neck cancer, tumor-infiltrating Tregs were found to be associated with good clinical outcome possibly because of controlling the harmful inflammatory reaction which otherwise may lead to tumor progression (Badoual 2006). Whereas, recruitment of Tregs in ovarian carcinoma (Curiel et al. 2004), hepato-cellular carcinoma (Gao et al. 2007), NSCLC stage I patients (Petersen et al. 2006), prostate cancer (Knutson et al. 2006)is associated with poor clinical outcome of patients. In some specific cases, the prognostic value of Tregs is dependent on infiltration in different areas of the tumors. For example, the high density of Ti-Treg in lymphoid aggregates is related with higher risk of relapse and a shorter relapse-free survival whereas the presence of Ti-Treg within tumor beds is not associated with the clinical outcome in primary breast cancers (Gobert et al. 2009). Surprisingly, there are also cases in which Tregs are not associated with the clinical outcome of the cancer patients. For example, in glioblastoma patients, Tregs do not have strong prognostic significance (Jacobs, Joannes F M et al. 2010; Heimberger et al. 2008). In anal squamous cell carcinoma, Tregs were not associated with clinical outcome of patients (Grabenbauer et al. 2006).
Several factors can be considered responsible for these discrepancies. An important issue can be the inability to identify individual functional Tregs easily. Only subsets of the T cells identified as CD4+CD25+ and are functionally suppressive Tregs. Remaining are mostly activated effector T cells. Confirmation of analysis of Tregs needs more markers other than FoxP3 like CTLA-4, GITR which are also expressed by the activated effector cells (Shevach 2002; Zou 2006; Bach, François Bach 2003). Devoid of the strong identity marker or unique set of markers makes it unable to detect the exact effect of the Tregs on clinical outcome of cancer patients. Markers CD25 and FoxP3 which are known to be expressed by Tregs, are also expressed in lower levels by the conventional CD4+ T cells upon activation. Based on the expression of the markers, the subset of Tregs may have different impact on the prognostic importance. The coexistence of the Tregs and PD-1+ TILs was found to be associated with poor survival in breast cancer (Ghebeh et al. 2008). High expression of PD-1 on lymphocytes and FoxP3+ Tregs has found to be deleterious for the patients with ccRCC (Kang et al. 2013).
Second, the function of Tregs seems to be different according to the cancer type. Tregs are thought to be preventing harmful inflammatory reaction and cancer progression and thus are responsible for good prognosis but in ovarian carcinoma Tregs are linked to the suppression of anti-tumor immune response and thus account for poor survival of patients (Curiel et al. 2004). Location in the tumor tissue and stage of cancer are also important factors determining the prognostic importance of Tregs in cancer. This can be observed in early-stage B cell lymphoma (Elpek et al. 2007a), advanced stage ovarian carcinoma (Leffers et al. 2009), early stage NSCLC patients (Petersen et al. 2006).

Table of contents :

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
1.3.2.1. General characteristics of TLS
1.3.2.2. 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

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