Immunotherapy Resistance Mechanisms in Renal Cell Cancer

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Immunotherapy Resistance Mechanisms in Renal Cell Cancer Katarzyna Kaminska1,*, Gabriel Wcislo1, Anna M. Czarnecka1, Salem Chouaib2 and Cezary Szczylik1 1 2

Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Warsaw, Poland; Institut National de la Santé et de la Recherche Médicale (INSERM U753), Institut Gustave Roussy, Villejuif, France Abstract: The successful treatment of renal cancer remains a therapeutic challenge. Clear Cell Renal Cell Carcinoma (ccRCC) is resistant to conventional radio and chemotherapy, but complete response has been observed after immunotherapy with high-dose interleukin-2 (IL-2) and interferon (IFN)-α. Nevertheless, immunotherapy strategies have shown response rates in the range of 5 to 10%. For the past 20 years, the mechanisms of treatment resistance have been studied, and immune escape of tumours in cancer development and spread has been a broadly investigated phenomenon. Multiple studies have revealed that genomic abnormalities of ccRCC promote the loss of major histocompatibility complex (MHC) molecules on the renal cancer cell surface, resulting in immune response resistance. Studies have shown that IFN-α-induced signalling pathways are deregulated in ccRCC cells and promote immune escape. Polymorphisms of multiple genes, including STAT3, have been shown to trigger immune-response deregulation. Investigation and understanding of the mechanisms of renal cell cancer immunotherapy resistance are extremely important for the design of rational combinatorial approaches and other novel therapies in the future. This mini-review focuses on immunotherapy resistance mechanisms in ccRCC.

Keywords: Renal cell carcinoma, immunotherapy resistance, renal cell cancer chemotherapy, renal cell cancer radiotherapy, IL-2 induced immunotherapy, IFN induced immunotherapy, TKI induced immunotherapy. RENAL CELL CARCINOMA The Renal Cell Carcinoma (RCC) is considered the most common urological tumour and accounts for almost 3% of human malignancies [1]. Several histological subtypes of this heterogeneous entity are associated with different molecular aberrations and clinical outcomes [2,3]. Clear-cell renal cell carcinoma (ccRCC) is the predominant subtype of RCC and affects up to 60,000 patients annually in the US; mortality was 13,500 in 2012 (Atlanta, GA: Cancer facts and figures 2011; American Cancer Society 2012.). Approximately 65,000 new cases of RCC were diagnosed, and more than 2500 deaths were reported in the European Union in 2012 [4]. Within Europe, the highest incidence of RCC has been reported in the eastern region, primarily in the Czech Republic and Poland. The causes of regional differences in morbidity are not known [4]. CcRCC is characterized by high metastatic potential, with a prolonged asymptomatic course. Metastatic disease develops in almost 50% of patients within five years of primary diagnosis [5]. In 25– 30% of patients with ccRCC, metastases are diagnosed synchronously with primary tumour. Only 10% of patients diagnosed with metastatic ccRCC survive more than five years. In the population of patients with localized disease, up to 60% will survive five years [6,7]. IMMUNE RESPONSE RESISTANCE MECHANISMS Cancer immune surveillance is considered an important host-protection process to inhibit carcinogenesis and to

*Address correspondence to this author at the Laboratory of Molecular Oncology, Military Institute of Medicine, Warsaw, Szaserow 128, 04-141 Warsaw, Poland; Tel: +48 - 22 - 681 71 72; Fax: +48 - 22 - 610 30 98; E-mail: [email protected] 2212-389X/13 $58.00+.00

maintain cellular homeostasis. In the interaction of host and tumour cells, three essential phases have been proposed: elimination, equilibrium and escape (Burnet 1957). According to this theory, cancer cells develop more often than tumours. Cancer cells are constantly eliminated by the immune system. Innate immune responses, such as natural killer cells, can initially eliminate Nascent transformed cells. During tumour progression, though an adaptive immune response can be provoked by antigen-specific T cells, immune selection produces tumour cell variants that lose major histocompatibility complex class I and II antigens and decrease tumour antigens. Finally, tumour-derived soluble factors facilitate the escape from immune attack, allowing progression and metastasis [8]. Even short-term disturbances in immune response may enable proliferating cancer cells to reach a high number. Evidence for the existence of immune surveillance is supported by epidemiological studies, which have shown that patients with immuno-deficiencies develop lymphoblastic lymphoma and Kaposi's sarcomas more often than the general population [9,10]. Further studies have revealed that the immunological deficiencies in patients result in a high rate of pathogen-related cancer development, including bacteria-induced tumours such as gastric cancer induced by Helicobacter pylori [11]; virus-induced lymphoma by Epstein-Barr virus [12]; Kaposi 's sarcoma, by human herpesvirus 8 [13]; and cervical cancer, by HPV [14]. Moreover, evidence for the immune system’s contribution to carcinogenesis is confirmed by the observations of immunocompromised transplant patients who develop multiple cancers [15,16]. Cancer immuno-editing theory states that all cancers in the early stages of development are immunogenic, causing the reaction of the immune system [17]. Accumulating evidence indicating that tumours develop mechanisms ©2013 Bentham Science Publishers

248 Current Signal Transduction Therapy, 2013, Vol. 8, No. 3

Table 1.

Kaminska et al.

Molecular mechanisms of tumour cells evading the immune recognition CTL T-cytotoxic lymphocytes; NK– natural killer cells. Mechanisms

Ref.

Reduction or absence of the expression of major histocompatibility complex classes I and II

[18,19]

Loss of tumour antigens

[20,21]

Impairment of proteasome function or ATP-dependent transporter proteins TAP peptide

[22]

Lack of co-stimulatory signals, such as B7 or CD40 molecules, on the surface of tumour cells

[23,24]

Aberration in expression of adhesion molecule

[103]

Impaired expression of Fas receptor and/or Fas ligand, leading to apoptosis of T - cytotoxic lymphocytes (CTL) and/or natural killer cells (NK)

[25-27]

Synthesis and secretion of immunosuppressive agents

[28,29]

Expression of TRIAL on tumour cells that leads to apoptosis of T lymphocytes

[30]

Clonal exhaustion of T cells or activation induced cell death

[31]

allowing them to circumvent immuno-surveillance and escape immune system control is emerging (Table 1) [17]. In the last two decades, a number of tumour "escape" mechanisms have been reported. These include: 1. The reduction or absence of the expression of major histocompatibility complex classes I and II - (MHC I and II) [18, 19] 2. The loss of tumour antigen presentation [20, 21] 3. The incorrect processing of intracellular antigens (impairment of proteasome function or ATP-dependent transporter proteins TAP peptide ) [22] 4. The disruption of co-stimulatory signalling molecules, including B7 and CD40 receptors [23,24] 5. The impaired expression of the Fas receptor and/or Fas ligand on T-cytotoxic lymphocytes (CTL) Natural killer cell (NK) [25-27] 6. The synthesis and secretion of immunosuppressive agents, such as IL -10, TGF - β, PGE2, blocking the immune response [28,29] 7. The expression of TRIAL (TNF-related apoptosis-inducing ligand) on tumour cells, which leads to apoptosis of T lymphocytes [30] 8. The chronic stimulation of specific T cells leading to clonal exhaustion or death (activation-induced cell death – AICD) [31] RENAL CELL CANCER IMMUNOTHERAPY Poor efficacy of radio and chemotherapy in RCC has drawn attention to other treatment modalities such as immunotherapy. The first immunotherapy trial for renal cancer was recorded in 1914, when the New York surgeon WB Cooley published a study assessing the long-term effects of the application of a bacterial-toxin mixture to patients with renal tumours (Colley 1914). Immunotherapy utilizing IL-2 or IFN-α is now registered in RCC treatment in the US

and EU [32-35]. Two recombinant forms, rIFN-α-2a and rIFN-α-2b, are available for clinical use; Roferon (rIFN-α2a) is more immunogenic than Intron A (rIFN-α2b). Th1 cytokine production is induced by IFN-α, and promotes antitumour cytotoxicity [36]. IL-2 is a growth/differentiation factor inducing and maintaining the cytotoxicity of NK and T cells [37]. Cytokine treatment, called nonspecific immunotherapy, induces nonspecific anti-tumour activity. IL-2 activates natural killer (NK) cells, and IFN-α promotes the maturation of antigen-presenting cells (APC). IL-2 indirectly limits tumour escape mechanisms, such as defective tumour cell expression of Class I or II molecules or expansion of regulatory T cells. Indirect effects of IL-2 on the tumour microenvironment are associated with T-cell infiltration during the global delayed-type hypersensitivity response. As a result, the use of IFN-α or IL-2 treatment regimens may results in a reduction of tumour burden by more than 50%. Unfortunately, the objective response rate (partial or complete) is in the range of 5 to 20% [38-41], and the median overall survival (OS) of responsive patients is about four months longer than non-responders (Rini, Weinberg et al. 2004). Further subgroup analyses revealed that performance status (ECOG) is the most important predictor of IFN-α response [42]. Moreover, the best outcomes were observed in patients with pulmonary or lymph-node metastases, while patients with liver or bone metastases showed a low percentage of objective response. During the IFN-α treatment, more that 30% of the patients developed anti-IFN-α antibodies. The production of antibodies leads to neutralization of IFN and inhibits immune response and anti-tumour toxicity. The development of anti-IFN antibodies was associated with RCC relapse short response and survival [43,44]. Immunotherapies other than IFN were tested. Broad clinical studies demonstrated that IL-2 had a response rate of 15 to 30%, with approximately 5% complete responses; median survival was reported between 6 and 19 months [45 46]. However, use of high-dose IL-2 is limited by its toxicity, which can cause hypotension, cardiac arrhythmias, metabolic acidosis, renal failure, neurotoxicity and dermatologic complications. Between 1–5% mortality was observed [47].

Immunotherapy Resistance Mechanisms in Renal Cell Cancer

High-dose IL-2 may be administered in a facility that is prepared to provide blood pressure support, but treatment candidates have excellent organ function and a good or intermediate prognosis by Memorial Sloan-Kettering Cancer Center (MSKCC, New York, New York) criteria. Other trials have shown that patients receiving low dose IL-2 suffered significantly fewer side effects while maintaining the same OS. Although IL-2 was more clinically active at maximal doses, this did not produce an overall survival benefit [47, 48]. Combined therapy of IL-2 and IFN-α exhibited longer median recurrence-free survival compared to single-agent treatment, but overall survival did not differ between treatment arms [46]. All reported data confirms that both IL-2 and IFN-α are active agents in ccRCC, and that immunotherapy is still an option in RCC treatment [39,49]. To increase the efficacy of the immunotherapy, multiple agents were tested, including tumour-initiating lymphocytes, IL-4, IL-1β, IFN-γ, and lymphokine-activated killer cells that were co-administrated to enhance IL-2 therapeutic effect. Trials did not prove clinical benefits of synergistic usage of other immune-stimulants in RCC treatment [46]. IFN-α was administrated with IFN-β and chemotherapy (i.e., 5-Fu), but this did not benefit patients [42]. Only reduced-dose monoclonal antibodies against VEGF (bevacizumab) increased IFN efficacy in RCC patients [50]. Recent insight into tumour-host interactions has also prompted new immunotherapeutic strategies for RCC, including the investigation of vaccinations in ccRCC. In particular, the TroVax vaccine targeting the 5T4 antigen, a protein found on 85% of solid tumours, was expected to boost the immune response [51]. Researchers reported that this treatment resulted in longer PFS but no difference in OS [51]. More recently, the importance of immune regulation by APC and regulatory Treg cells in ccRCC has been investigated. Primarily in mice models, researchers demonstrated that depletion of Tregs using anti-CD25 antibodies evoked effective anti-tumour immunity [52]. In RCC patients, elimination of Tregs followed by vaccination with tumour RNA-transfected dendritic cells (DCs) led to improved stimulation of tumour-specific T cells [53]. The most advanced agent in RCC immunotherapy is nivolumab, which acts as an immuno-modulatory ligand, blocking activation of the receptor PD-L1. This therapy was developed due to high levels of RCC cell production of the immunosuppressiveprogrammed death-ligand 1 (PD-L1). This is a ligand for the T-cell checkpoint molecule PD-1 that inhibits activated T cells and down-regulates the anti-tumour response. MECHANISMS OF IMMUNOTHERAPY RESISTANCE IN ccRCC The limitations in immunotherapy efficacy are a result of multiple intrinsic and therapy-inducted resistance mechanisms. Wolf et al. [54] observed statistically significant enhanced gene expression of pathway B-cell receptor (BCR), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and T-cell receptor in ccRCC patients when compared to a healthy donor. All these pathways are well-known inhibitors of immune response involved in the modulation of immune system functions with CTLA-4 [55]. Observed discrepancies suggested a primordial defect of the immune system in patients who develop RCC and immunotherapy resistance.

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Down-regulation or lack of expression in MHC class I and II molecules is believed to be a predominant tumour-specific cell-mediated immune effector mechanism, which determines immune escape in ccRCC [18,19]. Studies based on RCC tumour explants have revealed low expression of HLA class I on the RCC cell, which may represent an immune escape mechanism of RCC [56]. Studies based on an in vitro RCC model revealed that CIITA (human gene encoding a protein called the class II major histocompatibility complex transactivator) transfection significantly delayed tumour growth when injected into BALB/c mice [57]. However, compared to other investigated cancer cell lines, the renal cancer cell line is characterized by low stability of CIITA expression. Furthermore, ex vivo-isolated cells from CIITA tumour-bearing mice displayed retarded tumour growth, and showed an almost complete loss of MHC-II expression. Although CIITA-RENCA tumour cells (transfected renal cell line) could not be fully rejected, they grew in vivo with significantly reduced kinetics compared to parental cells (not transfected with CIITA) [57]. Kren et al. [58] evaluated the correlation between HLAG and HLA-E expression and the prognostic significance in RCC patients. Authors demonstrated that up-regulation of HLA-G is connected with a worse prognosis, and increased expression of HLA-E carried a better prognosis [58]. The majority of RCC-infiltrating myeloid cells co-express MHC class II molecule [59] and variable levels of PD-L1, which play a major role in suppressing the immune system. RCCinfiltrating macrophages mediate immunosuppression also due to up-regulation of 15-lipoxygenase-2 (15-LOX2) [59]. Inhibition of 15-LOX2 decreased the synthesis of the immunosuppressive cytokine IL-10 and monocyte chemoattractant protein (CCL2), which provide enhanced recruitment of blood myelomonocytic cells. Targeting 15-LOX2 is a potentially valuable measure for limiting cancer-related inflammation mediated by CCL2, and for attenuating immunosuppression mediated by tumour-associated macrophages (TAMs). This measure thereby enhances anti-tumour immune response in patients with advanced RCC [59]. These findings underscore the relevance of IL-10-producing TAMs to immunosuppression observed in patients with late-stage cancer. TAMs can promote the expression of forkhead box P3 (FOXP3) and cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). CTLA-4 plays a key role in restraining the adaptive immune response of T cells toward a variety of antigens, including tumour-associated antigens (TAAs) [55] and FOXP3 function as a master regulator in the development and function of regulatory T cells [60]. The direct and indirect influences of TAMs in promoting local immunosuppression and RCC tumour evasion has been demonstrated. The results suggest that the 15-LOX2/15(S)HETE pathway is a key player in this mechanism. Hence, new therapeutic approaches should focus on the manipulation of the 15-LOX2 mediated in patients with advanced RCC [59]. Pre-incubation of peripheral blood mononuclear cells (PBMCs) with RCC cell line cells resulted in decreased cytotoxic potential of NK cells [61]. It was demonstrated that pre-incubated NK cells overexpress a CD94 surface marker, which recognizes MHC class I and further blocks cytotoxicity of NK cells [61]. IL-15 has been identified as a


key mediator in this mechanism. Researchers found that IL15 enhances the cytotoxicity of NK cells both pre-incubated and co-cultured with RCC cells [61]. The blocking of the CD94 receptor due to an increased level of IL-15 may enhance NK cytotoxicity in RCC patients and may augment the immune response against tumour cells [61]. Inhibitors of DNA methyltransferase 1 may have clinical relevance for immune modulation by the augmentation of cytokine effects and/or expression of tumour-associated antigens, as demonstrated in an in vitro RCC model [62,63]. Another surface marker, CD70, was proved to play an important role in immune escape in RCC [64]. Co-culture of a T-cell line with RCC cells induced significant apoptosis of immune cells [64]. The activation of the CD70 receptor on T cells resulted in apoptosis. Inhibition of the CD70 receptor in the presence of a recombinant soluble CD70 completely blocked this process [64]. Since RCC cell lines express the CD70 ligand but not the CD70 receptor, and in co-culture RCC cells induce apoptosis in MOLT-4 T cells, it is highly possible that this mechanism is involved in complete ccRCC immune escape [64]. Further investigation revealed that other signalling pathways are involved in T-cell apoptosis. RCC cell lines secrete Fas ligand, which may protect tumour cells from immune-mediated elimination by Fas-expressing T cells, as FasL induces T-cell apoptosis [65]. Blockage of the Fas pathway by anti-FasL Abs or by treating the T cells with an inhibitor of caspase-8, led to a 50% inhibition in T-cell apoptosis when incubated with RCC cells [65]. FasL RCC cell lines also overexpress gangliosides, which can enhance apoptosis. Das et al. observed that the apoptosis of primary T cells occurs via a receptor-independent pathway by a mechanism that involves ganglioside-mediated initiation of the mitochondrial permeability [65]. In summary, receptordependent and receptor-independent mechanisms act collectively to defeat the lymphocytes, which can promote the progressive growth of the RCC tumour [65]. MECHANISMS OF IFN-INDUCED THERAPY RESISTANCE IN ccRCC

IMMUNO-

Recent microarray analyses revealed that the observed immuno-resistance origins from transcription deregulation in renal cancer cells rather than is developed during immunotherapy [54]. No statistical differences were observed in gene expression of the peripheral blood lymphocyte population (PBL) collected from patients before and after treatment with IL-2, IFN-α and autologous dendritic cell (DC) tumour vaccination [54]. This result confirms that immunotherapy in metastatic ccRCC does not modulate the immune system through influence on lymphocytes to develop drug resistance. Modest changes were reported in levels of proinflammatory cytokines in peripheral blood, and it was hypothesized that the treatment influences cytokine secretion by cells other than immune cells. At the same time, responding patients showed up-regulation of the Hypoxiainducible factors α (HIFα) and class III receptor tyrosine kinase (FLT3) pathways. Cluster analysis of genes in these pathways allowed discrimination between “non-responder” and “responder” patients [66,67]. Moreover, IFN-α promoted up-regulation of HLA-G surface expression on RCC cells [68]. HLA-G mediated suppression of T-cell and NK cell [69,70] HLA-G molecules, protected tumour cells from

Kaminska et al.

immune attack [68, 71] and reduced susceptibility to CTL, LAK and NK cell-mediated cytotoxicity [68, 71]. Using an RCC in vitro model, researchers showed that IFN’s resistance has an unclear background, since the observed resistance is not due to structural aberrations of IFN-α receptor or failure to initiate the gene-inducing and anti-viral effect of IFN-α [72]. Researchers investigated IFN-α biological action and determined that this agent is a therapeutic factor. Nevertheless, discrepancies in in vitro studies on RCC [73] cell lines and limited clinical benefit led to a question about the basis of observed heterogeneous effect of the same agent on the same type of cancer. One suggestion is that there are more pathways involved in apoptosis induced by IFN-α [73]. Up-regulation of the Fas pathway is involved in activation of the cell-death pathway in RCC cell lines [74], and interferons up-regulate Fas in RCC cell lines [75]. Results obtained by Kelly et al. suggest that the IFN-α treatment Fas-dependent pathway as well as alternative is involved, resulting in apoptosis of RCC cells [73]. Despite considerable efficacy, in vitro studies show that IFN-based treatment is not as successful. Recent evidence suggests that Fas receptor activation and apoptosis can be inhibited by Bcl-2 [76,77]. Kelly et al. suggested that targeting Bcl-2 synergistically with IFN-α treatment might improve therapy. Studies from another groups revealed that the re-expression of the genes that are silenced due to methylation is needed to overcome the resistance [62,63]. The suppressor of cytokine signalling 3 (SOCS3), which negatively regulates the signal transducer and activator of transcription 3 (STAT3) [78] and IFN-α signalling [79], is another key factor in RCC resistance to IFN-α treatment [80]. SOCS3 expression level was significantly increased after IFN-α stimulation and SOCS3 siRNA treatment resulted in IFN-α-mediated anti-proliferative effects in vitro and in vivo [80]. The authors suggest that the silencing of SOCS3 expression is a possible strategy to restore sensitivity to IFN-α in resistant cells [80]. Other SNPs than the previously described SNP rs1905341 in STAT3-2 gene and low expression of SOCS3 could be responsible for the lack of response in RCC patients treated with IFN-α. Reconstitution of STAT2 expression in RCC cell lines restored the apoptotic effect of IFN-α [81]. Shang et al. demonstrated that low expression of STAT1 is associated with the resistance of RCC to IFN-α, and the restoration of its expression may increase the susceptibility of RCC to IFN-α-based immunotherapy [82, 83]. Researchers demonstrated that STAT1, TRAILR1, IRF-7 and DAPK genes undergo epigenetic changes mediated by DNA methyltransferase 1 (DNMT1), which is essential for various actions of IFNs. Hypermethylation of these genes may confer growth advantage through resistance to endogenous IFNs [84-87]. Epigenetic editing of gene expression by aberrant methylation of DNA helps RCC tumour cells escape attack from the innate and acquired immune systems. Resistance to anti-proliferative effects and apoptosis induction by IFNs was postulated to result from the silencing of IFN response genes by promoter hypermethylation; therefore, inhibitors of DNMT1 may have clinical relevance for immune modulation by augmentation of cytokine effects and/or expression of tumour-associated


Table 2.


251

Molecular aberration resulting in RCC immune resistance or immune escape;

Gene

Factor

Abnormality in Resistance

Cell type

Abnormality/Resistance

Ref.

CAIX

Catalyses the reversible hydration of carbon dioxide to carbonic acid

Up-regulation

Tumour cells

Better response on IL-2 based therapy

[2,3]

VHL

Tumour suppressor

Mutation

Tumour cells

IFN-α resistance

[91]

HLA-G

Immune auto-tolerance

Up-regulation after IFN-α treatment

Tumour cells

Protects tumour cells from immune attack; IFN-α resistance

[68,71]

HIF-1α; FLT3

HIF-1α: adaptation to low-oxygen conditions FLT3: cell survival, proliferation, and differentiation.

Up-regulation after immunotherapy

Peripheral blood lymphocytes

Better outcomes from IL-2; IFN-α treatment

[54]

BCR; CTLA4; TCR

Immune response

Up-regulation in RCC patients compared to healthy individuals

Peripheral blood lymphocytes

IL-2; IFN-α

[54]

CD94

Surface marker which recognizes MHC I

Up-regulation

Tumour cells

Blocking of CD90 increased cytotoxicity of NK cells

CD70

Immune activation

Constitutive expression

Tumour cells

Induction of CD70 receptor on T cells resulting in apoptosis

[64]

CD70

Immune activation


T cells

Immune escape

[64]

Fas ligand

Regulation of the immune system


Tumour cells

T-cell apoptosis

[65]

STAT3

Differentiation of the TH17 helper T cells, cell growth, apoptosis

Single nucleotide polymorphism

Tumour cells

Associated with better response to INF-α based therapy

[104]

SOCS3

Suppressor of cytokine signalling

Up-regulation

Tumour cells

IFN-α resistance

[80]

CIITA

Immune system functions

Down-regulation

Tumour cells

CIITA tumour-mediated CD4 T-cell priming is required for the generation of anti-tumour cytolytic T lymphocytes

[61]

STAT1, TRAILR1, IRF-7, XAF1, RASSF1, DAPK

STAT1 – activation of IFN response; TRAILR1 – immuno-surveillance, IRF-7- regulator of IFNs, XAF1 – apoptosis, RASSF1A – cell proliferation, differentiation, motility and apoptosis, DAPK –inhibition of cell adhesion/migration and promotion apoptosis

Hypermethylation

Tumour cells

Inhibition of apoptosis induced by IFN

[62,63]

HLA I

Control of the immune response

Down-regulation

Tumour cells

Immune escape

[56]

CAIX carbonic anhydrase IX; VHL - von Hippel-Lindau; HLA-G - histocompatibility antigen, class I, G; HIF-1α - Hypoxia-inducible factors α; FLT3 - class III receptor tyrosine kinase, BCR - B-cell receptor; TCR - T-cell receptor; CTLA-4 - cytotoxic T lymphocyte-associated antigen 4; CD94 - C-type lectin receptor; CD70 - tumour necrosis factor ligand; STAT1/3 - Suppressor of cytokine signalling 1/3; SOCS3 - cytokine signalling suppressor of cytokine signalling 3; CIITA - gene encoding an MHC class II transactivator, TRAILR1 – gene encoding tumour necrosis factor receptor superfamily member, IRF-7- virus-inducible cellular gene, XAF1 – gene encoding XIAP-associated factor 1, RASSF1 - gene encoding a protein associated to the RAS; DAPK - death-associated protein kinase gene; HLA I - histocompatibility antigen class I.

antigens [62]. Rue et al. showed that the overexpression of XAF1 plays a significant role in apoptosis induction by IFNs [62]. Further analysis of cRNA array revealed another 19 genes with a possible effect on immune responses that were increased at least four-fold in DNMT1-depleted RCC cells [62]. Studies revealed that the silencing of the RASSF1A gene abolishes the resistance to apoptosis induction by IFNs treatment [63]. Other findings suggest that epigenetic changes play a crucial role in RCC treatment, allowing suppression to emerge as an important contributor to the

development of clinical neoplasia. Finally, microarray studies of IFN-stimulated gene expression patterns suggest that subtle differences in transcription profiles may contribute to differences in IFN responsiveness [88]. The authors conclude that factors determining clinical response to IFN remain elusive, but resistance of RCC to IFN-alpha is associated with the lack of Jak1, Tyk2 and STAT1 expression and defective Jak-Stat activation, but not with deficiency of IFN receptors or suppressors of cytokine signalling induction [88].


MECHANISMS OF IL-2-INDUCED IMMUNOTHERAPY RESISTANCE IN ccRCC In an IL-2 immunotherapy context, carbonic anhydrase IX (CAIX) has been identified as a potential response marker. High expression of CAIX in primary tumour has been correlated with response to IL-2, survival and pathologic risk categorization [2,3]. CAIX expression is mediated by the HIF-1 and is dependent on mutation in the von HippelLindau (VHL) gene. Tumours with VHL mutation show higher CAIX expression than those without VHL mutations. VHL is mutated in almost in 80% of patients with RCC [4,89], and high CAIX expression has been identified in more than 85% of cases [4]. According to reports, CAIX high expression correlates with positive response to IL-2, therefore complete remissions should be observed in 85% of cases, not 5 to 10% [90]. Nevertheless, it has been suggested that mutation of the VHL gene is involved in IFN-α resistance [91]. As assessed by IFN-γ secretion, NK degranulation and cell lysis, the blocking of human leukocyte antigen (HLA)-I-specific inhibitory NK receptor interactions pVHL-transfected cell lines produced a weaker activation of NK cells and substantially increased lysis of RCC-pVHL [91]. The observed genetic aberration in RCC can predestinate this type of neoplastic change to be resistant to immunologic treatment. Moreover, RCC with a papillary, no alveolar, type and/or more than 50% granular features responded poorly to IL-2, and should be considered for alternative treatments [10]. Histological features are a consequence of genetic alterations. Table 2 summarizes known genes that may contribute to the phenomenon of resistance mechanisms in renal cancer. Their modification may have therapeutic significance in RCC immunotherapy. MECHANISMS OF TKI-INDUCED LOGICAL RESISTANCE IN ccRCC

IMMUNO-

Targeted therapy agents affect neutrophil migration, T lymphocyte-dendritic cell cross talk, dendritic cell maturation, and immune cell metabolism and reactivity. The inhibiting vascular endothelial growth factor receptor VEGFR (sorafenib, sunitinib, pazopanib and axitinib) and the mammalian target of rapamycin (mTOR) (temsirolimus and everolimus), are particularly effective [92]. Sorafenib, a multi-kinase inhibitor inter alia FLT3, is capable of modulating the immuno-biological activity of dendritic cells and a murine regulatory macrophage population [93,94]. Sorafenib (10 µm) inhibits proliferation of T cells and, at higher concentrations, T-cell apoptosis [95]. The maximum concentration of sorafenib was more than 15 µm in the serum of patients, so the investigated concentrations are lower than those for clinical use [96]. Further investigation showed that sorafenib (10 µm) significantly inhibits the macrophage viability [97]. Moreover, sorafenib suppressed the CD80 expression and function of activated macrophages. Sorafenib-treated macrophages exhibited extensive development of cytoplasmic vacuoles, which suggests induction of autophagy [97]. Thus, it should be kept in mind that a high dose of sorafenib leads to unrecoverable immunosuppression, and the dose-escalated strategy carries a risk for the longterm treatment of mRCC. The frightening conclusion from these findings is that sorafenib, and probably other TKIbased treatments, may induce immuno-resistance. Therefore,

Kaminska et al.

the blockade of one or few oncogenic pathways may lead to disease progression and increased tumour burden. Observed resistance may be the tumour’s attempt to overcome the blockade of the pathway that allows its development. Sunitinib was not studied in such a context, but as these two tyrosine kinase inhibitors have similar modes of action, we hypothesized that the effect of sunitinib treatment could be similar. CONCLUSION AND FUTURE DIRECTIONS The immune system plays a significant role in the control of tumours. Growing knowledge has allowed the development of new immunotherapies and the use of multiple tumour antigens with the potential to induce a greater immune response. IL-2 and interferon-α were the only effective therapies against ccRCC before the appearance of therapeutic options such as the novel agents that target the VEGFR and mTOR. IL-2 remains the only treatment capable of curing advanced RCC, albeit in few patients. Randomized phase II and III trials have proven that high-dose, intravenous bolus IL-2 elicits a superior response rate compared to regimens that involve either low-dose IL-2 and IFN-α, intermediate- or low-dose IL-2 alone or low-dose IFN-α alone [98]. Despite recent advances, there are still unmet needs among patients in the adjuvant setting, those with poor prognostic factors and those who have progressed on prior targeted therapies and/or immunotherapy. Improved understanding of host-tumour immune interactions has led to the recent development of novel immunotherapeutic agents, including various vaccines and antibodies against immune checkpoint proteins (PD-1 and CTLA-4) [99]. Phase I and II trials of vaccination with allogeneic dendritic cell/tumour fusions in patients with metastatic ccRCC have also demonstrated immunological and clinical responses. T-cell modulating agents (e.g., PD-1 and CTLA-4 or soluble lymphocyte activation gene-3) and dendritic cell-activating toll-like receptor agonists have also shown encouraging evidence of efficacy. All recent studies suggest that new immunotherapy may be an effective approach for patients with ccRCC. A number of new strategies are currently under investigation, including adoptive cell transfer (ACT) with T cells modified to target proteins expressed by renal tumour cells such as MAGEA3/12, DR4 and TRAIL. ACT with autologous natural killer cells is also under investigation [100]. TAMs (tumourassociated macrophages) represent a promising and effective target for cancer therapy in RCC. Several strategies have been proposed to suppress TAMs recruitment, to deplete their number, to switch M2 TAMs into the anti-tumour M1 phenotype and to inhibit TAM-associated molecules. TAMs infiltration in RCC microenvironment contributes to cancer progression and metastasis by stimulating angiogenesis, tumour growth, cellular migration and invasion and epithelial-mesenchymal transition of RCC cancer cells in the development of tumour resistance to targeted agents [101]. Advances in the understanding of the nature of tumour antigens and their optimal presentation, and progress in the understanding of regulatory mechanisms that govern the immune system, should provide multiple novel ccRCC immunotherapy intervention strategies with increased specificity and fewer side effects [102].



CONFLICT OF INTEREST The authors indicate no potential conflict of interest.

[20]

ACKNOWLEDGEMENTS CS, AMC and KK are supported by the Military Institute of Medicine statutory founding 1/1744 (101), National Science Centre projects 2011/01/B/NZ5/02822 and 2011/01/B/NZ4/01602 and the Foundation for Polish Science TEAM project TEAM/2010-6/8. AMC is supported by the Ministry of Science and Higher Education "Juventus" grant CRU/WIM/275/2012. The authors acknowledge the support of the Scribendi, Inc. for professional editing and proofreading of this manuscript.

[21] [22] [23] [24]

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Received: December 03, 2013

Revised: January 22, 2014

Accepted: January 29, 2014

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