Curr Urol Rep (2015) 16:59 DOI 10.1007/s11934-015-0532-8
GENETICS AND MICROENVIRONMENT (X CATHELINEAU, SECTION EDITOR)
Inflammation and Cancer: What Can We Therapeutically Expect from Checkpoint Inhibitors? Johannes Mischinger 1 & Eva Comperat 2 & Christian Schwentner 1 & Arnulf Stenzl 1 & Georgios Gakis 1
# Springer Science+Business Media New York 2015
Abstract Programmed death-ligand 1 (PD-L1) is a cell surface protein which is mainly expressed on immune cells as well as on cancer cells and functions as a co-stimulatory molecule for T lymphocytes. It is capable of inducing apoptosis in T-cells via PD-1 which leads to impaired cytokine production and loss of cytotoxicity of activated T-cells. This represents a possible escape mechanism for cancer cells. Tumor infiltration by mononuclear cells and tumor aggressiveness was found to be associated with PD-L1 expression. In light of possible autoimmunological side effects, it remains currently unclear which patient will benefit most from this novel therapeutic approach. Furthermore, immunohistochemistry for PD-L1 has not been well standardized until now. In addition, the combination of chemotherapy with checkpoint inhibitors in different clinical settings needs to be established for the near future in order to avoid overtreatment and also unnecessary cost expenditures for the health care system.
Keywords Bladder cancer . Checkpoint inhibitor . Escape mechanism . PD-1 . PD-L1 . Prostate cancer
This article is part of the Topical Collection on Genetics and Microenvironment * Georgios Gakis [email protected] 1
Department of Urology, Eberhard-Karls University Tübingen, Hoppe-Seyler Strasse 3, 72076 Tübingen, Germany
2
Department of Pathology, Pitié-Salpêtrière Academic Hospital, Pierre and Marie Curie Medical School, Paris, France
Introduction In 2006, more than 1.7 million people died of cancer in Europe, while more than 3 million new cancer cases were diagnosed [1]. Until 2030, an increase from 14 to 21 million new cancer patients per year has been estimated with a trend towards increased mortality from 8 to 13 million people worldwide during this time period. Potential reasons for this development are multifactorial which include environmental and genetic factors as well as demographic changes especially in the Western countries with an excess in age and typical lifestyle [2]. Apart from these factors, more than 15 % of all malignancies can be related to infections, with about 1.2 million cases per year [3]. In the past, many different cancer entities have been associated with history of infection, i.e., gastric cancer (Helicobacter pylori), hepatocellular cancer (Hepatitis-B and -C virus), Kaposi-sarcoma/squamous-cell-carcinoma/nonHodgkin’s lymphoma (HIV), or Burkett’s lymphoma (Epstein-Barr virus) [4]. Cervical cancer is also attributed to viral infection but probably more due to the non- inflammatory oncogenic potential of HPV on cervical cells [5, 6]. In this regard, although distinct viruses have been found to be oncogenic which is supportive of the hypothesis that active oncogenes can be integrated into the host’s genome, only a subset of infected individuals will develop a malignant tumor. Therefore, this pathway does not provide a comprehensive explanation for inflammation-based cancer development and suggests the presence of other inflammation-mechanisms responsible for carcinogenesis [4]. Usually, chronic inflammation induces a rise of leucocytes and phagocytic cells which produce reactive oxygen and nitrogen substrates that exert cytotoxic properties. These two types can react to peroxynitrite which is a mutagenic agent that causes DNA damage in proliferating cells [7].
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In chronic inflammation, permanent tissue damage and restoration processes in the presence of peroxynitrite can lead to point mutations, deletions, or gene rearrangements [8•]. As an example, p53 mutations are found not only in tumors but also in tissues of chronic inflammatory disease, such as chronic inflammatory bowel disease or rheumatoid arthritis [9]. Furthermore, a constant secretion of macrophage migration inhibitory factor (MIF) by T lymphocytes and macrophages results in increased damage of the DNA. MIF is a cytokine that is capable of suppressing the transcriptional activity of p53. Permanent suppression of the function of the p53 gene in tumorinfiltrated tissue leads to excessive proliferation and cell viability. This results in a deficient host’s response to DNA damage and increased number of possible oncogenic mutations [10].
Inflammation and Prostate Cancer Prostate cancer represents the most frequent cancer entity in men with nearly 900,000 new cases and approximately 260, 000 deaths worldwide. The incidence is highest in Western countries [11]. Similarly to cervical cancer [12], there is evidence which suggests that prostate carcinogenesis can be related to viral infections. The human papillomavirus (HPV) has been detected in prostate cancer cells and perifocal tissue lesions [13]. Further investigations have shown no association between Chlamydia trachomatis, HPV-16 or HPV-33 seropositivity and prostate cancer development. Intriguingly, a significant inverse correlation between positive serum levels of anti-human herpesvirus 8 (HHV-8) antibody concentration and prostate carcinogenesis could be found [14]. In addition, the herpesvirus 2 could be detected in a subset of prostate cancer specimens after radical prostatectomy but patients with prostate cancer showed no higher levels of herpes simplex virus type 2 antibodies compared to patients with benign hypertrophy of the prostate [15]. In contrast, a positive serological status for Trichomonas vaginalis was positively associated with a higher risk for prostate cancer development as well as extraprostatic cancer growth and increased mortality [16]. Moreover, the Epstein-Barr virus was found in prostate cancer tissues, but not in healthy prostate specimens [17]. Inflammation of the prostate can also be caused by acute or chronic bacterial as well as abacterial infections which may result in chronic pelvic pain syndrome or subclinical inflammatory prostatitis [18]. Typical tissue characteristics related to prostatitis are commonly described in histopathological reports after surgical treatment of the prostate, i.e., prostate biopsy or transurethral resection of the prostate [19, 20]. A recent meta-analysis of 20 case-control studies reported a significantly increased risk for developing prostate cancer when
Curr Urol Rep (2015) 16:59
patients suffered from prostatitis in the past [21]. In older men, proliferative inflammatory atrophy (PIA) signifies large parts of the prostate which histologically corresponds to areas of prostatic atrophy due to inflammation and constitutes a risk factor for prostate cancer development. As a consequence of cellular damage, proliferating atrophic epithelial cells are regenerated and are capable of inducing prostatic intraepithelial neoplasia, a precursor lesion for prostate cancer [22].
Inflammation and Bladder Cancer In Western countries, bladder cancer represents the sixth most frequent cause for cancer death in men and the eight most common cause in women. In Germany, the incidence of bladder cancer in 2010 amounted to the fourth most common cancer in men and 14th most common malignancy in women. In the same year, it was the 10th most common cause for cancer death in men and 14th cause of death in women [23]. Non-muscle-invasive bladder cancer is characterized by a high recurrence and low progression rate [24]. As a consequence, treatment of bladder cancer induces the highest costs of all malignancies in Western health care systems [25]. As a result of improved bladder cancer management in the USA, a significant increase in 5-year survival rates has been observed for all urothelial tumor stages except for patients with metastatic disease [26]. In metastatic bladder cancer, effective tumor suppression necessitates an intact immune system [27, 4]. As an example, although invasive urothelial cancer cells have the ability to penetrate into the subepithelial tissue of the bladder, further invasion can be effectively prevented by intravesical instillation of Bacille CalmetteGuerin (BCG), an attenuated mycobacterium which induces bladder wall inflammation [28]. Although the exact pathway of bladder cancer cell invasion and formation of distant metastatic clones has not been sufficiently understood, an impaired immune response seems to be a requisite to any process of metastasis formation [29]. It has been consistently demonstrated for patients with invasive urothelial cancer that an increased preoperative level of C-reactive protein (CRP) is associated with inferior survival after radical surgery or first-line chemotherapy [30•, 31]. Immunohistochemical studies of patients treated with BCG for highgrade or early-invasive bladder cancer have shown that the relationship between the number of macrophages infiltrating into the cancer area and those in the tumor surrounding lamina propria is of prognostic value [32]. In this regard, macrophages can show a divergent way of immunologic action. There are two distinct types of macrophages with pro-inflammatory (type 1) and antiinflammatory (type 2) properties. In in vitro studies, cell viability of T24 cancer cells was found to be higher in T24 cell/macrophages-2 co-cultures compared to T24/
Curr Urol Rep (2015) 16:59
macrophages-1 co-cultures. Interestingly, the inhibitory effect of macrophage-1-derived factors was suppressed by macrophage-2-derived factors while exogenous interleukin (IL)-10 reversed the effects of macrophage-1-derived factors [33]. An essential part of cellular immunity is constituted by CD4+- and CD8+-T-cells and natural killer cells (NKC). BCG is known to stimulate human peripheral blood mononuclear cells (PBMC) which lead to proliferation of effector cells which, in turn, exert a cytotoxic effect on bladder cancer cells. In this context, NKC and CD8(+) T-cells were found to be responsible for enhanced cytotoxicity induced by recombinant BCG-interferon (IFN)-alpha (rBCG-IFN-alpha). This enhanced effect is due to a higher capability of PBMC to secret interferon-gamma and interleukin (IL)-2. Conversely, the effect of rBCG-IFN-alpha could be reduced after application of neutralizing antibodies against IFN-alpha, IFN-gamma, and IL-2 [34]. Altogether, although the effects of immune cells on cancer cell apoptosis are not fully understood, macrophages seem to play a key role in the initiation of cancer cell apoptosis.
Escape Mechanisms of Urothelial Cancer Cells As for various other tumor entities, immunological escape mechanisms have also been described for bladder cancer. Distinct surface proteins on cancer cells have the ability to circumvent the cytotoxic cellular response of the immune system. Toll-like receptor 4 (TLR4) represents a member of the Toll-like receptor family which functions as a lipopolysaccharide (LPS) signaling receptor in urinary tract infections. An excessive release of LPS during septicemia (i.e., caused by an Escherichia coli infection) can enhance TLR4 signaling [35–37]. TLR4, originally found as an epitope on immune cells, has also been detected on tumor cells and is assumed to induce signaling pathways which protect tumor cells from the immune system [38]. Programmed death-ligand 1 (PD-L1) or B7-H1 is a cell surface protein which is mainly expressed on immune cells and functions as a co-stimulatory molecule for T lymphocytes. It is capable of inducing apoptosis in T-cells which leads to impaired cytokine production and loss of cytotoxicity of activated T-cells. This enables tumor cells to escape the cytotoxic effects of the immune system [39, 40]. Bladder cancer cells also show a high expression of TLR4 and PD-L1 on their cell surface. Activation of the TLR4 signaling pathway in bladder cancer cells upregulates PD-L1 expression which could be a potential target for inhibiting tumor escape mechanisms. This regulation is significantly suppressed by ERK (or JNK) inhibitors, which can restore sensitivity of T24 cells to cytotoxic T-cell (CTL)-mediated killing. These interactions represent a strategy for effective
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bladder cancer treatment. Interestingly in low-grade nonmuscle-invasive bladder cancer (NMIBC) cells, TLR4 expression is reduced compared to normal urothelial cells. The decline of TLR4 in patients with high-grade or muscleinvasive bladder cancer was even more pronounced. By contrast, patients with high-grade NMIBC exhibit significantly higher expression rates of PD-L1 and PD-1. Expression of PD-1 on tumor-infiltrating lymphocytes (TILs) and B7H1 on tumor cells showed a direct correlation [35]. Figure 1 outlines the interaction between cell surface proteins PD-1 and PD-L1 on lymphocytes and tumor cells. The expression of PD-L1 correlates positively with tumor stage. Among 280 high-risk bladder cancer cases, PD-L1 expression was found in 7 % of pTa tumors, 16 % of pT1, 23 % of pT2, 30 % of pT3/4, and even 45 % of patients with carcinoma in situ (CIS). In this context, tumor infiltration by mononuclear cells and tumor aggressiveness was associated with PD-L1 expression. Moreover, it was shown that patients who failed BCG therapy exhibited an extremely high density of B7-H1 within BCG granulomas which were found adjacent to the recurrent tumor tissue. The blockage of PD-L1 may also lead to an improvement of the host’s immune response especially in patients with BCG-refractory disease [41]. The effectiveness of this therapeutic approach could already be demonstrated in in vitro and in vivo tests. In a mice model for hepatocarcinoma, blockage of the PD-1/B7-H1 pathway with soluble PD-1 (sPD-1) expressed by an eukaryotic expression plasmid (pPD-1A) improved antitumor immunity. In addition, the secretion of IFN-gamma and TNF-alpha by lymphocytes was upregulated by sPD-1 blockade [42]. In 65 bladder cancer patients, B7-H1 expression was also significantly associated with a higher risk of postoperative tumor recurrence and inferior survival suggesting that the tumorassociated B7-H1 expression is an important prognostic factor in advanced tumor stages [43]. A recent study of 160 patients investigated the prognostic impact of PD-L1 expression in urothelial carcinoma (UC). PD-L1 positivity was evaluated using a mouse monoclonal anti-PD-L1 antibody on tumor cells (defined as ≥5 % staining of the tumor cell membrane) as well as on tumor-infiltrating mononuclear cells (TIMCs) and was correlated with clinical and pathological tumor
Fig. 1 Negative stimulatory effect of a cancer cell expressing PD-L1 on a T lymphocyte after binding to the major histocompatibility complex and its antigen on the T-cell receptor. Immune escape is mediated by simultaneous binding of PD-L1 to PD-1. Ag antigen, MHC major histocompatibility complex, PD-L1 programmed death-ligand 1, PD-1 programmed death-1, TCR T-cell receptor)
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characteristics. Only 20 % of the patients showed a positive PD-L1 expression on tumor cell membranes. Of 143 samples in which TIMCs could be verified, 40 % had positive PD-L1 expression on TIMCs. Interestingly, neither a history of smoking nor prior BCG therapy correlated with PD-L1 expression on tumor cells and TIMCs. In addition, there was no difference between PD-L1 positivity between non-invasive or invasive UC. In patients who developed metastases (M1) and were treated with systemic therapy, PD-L1 positivity on tumor cells could not be associated with overall survival (OS). By contrast, in patients with metastatic disease and positive PD-L1 expression on TIMCs, PD-L1 expression was an independent predictor of improved overall survival [44]. Notwithstanding, the PD-L1/PD-1 axis as a checkpoint for restoration of host immunity against tumor escape mechanisms has become a promising step towards durable remission in metastatic bladder cancer. Beneficial therapeutic effects have been already shown for various tumor entities, i.e., melanoma, lung and renal cancer. In light of possible autoimmunological side effects, it remains nowadays unclear which tumor patient will benefit most from this therapeutic approach. Furthermore, immunohistochemistry (IHC) for B7-H1 has not been well standardized, particularly due to the use of different antibodies and tissue preparation techniques, cut-off values, different clinical settings (primary vs. metastatic), and staining of tumor vs. immune cells. Patients with overexpression of B7-H1 showed improved clinical outcomes with anti-PD-1-directed therapy. However, since even patients with low expression levels of B7-H1 have also shown satisfactory clinical response rates to treatment, further research is necessary to better understand the role of the host’s immunological status on treatment response [45]. For patients with melanoma, renal cell carcinoma, and lung cancer, recent studies have shown that anti-PD-L1 and antiPD-1 therapies lead to significant response rates, even after multiple prior systemic therapies. Currently, anti-PD-1/PD-L1 antibodies, such as pembrolizumab and nivolumab, have been approved for the treatment of patients with metastatic melanoma. Furthermore, these two agents as well as diverse other anti-PD-1/L1 antibodies are also examined within clinical trials for the treatment of other solid malignancies such as bladder, lung, breast, and renal cancer [46]. In this regard, possible sequential therapeutical approaches of chemotherapy and immunotherapy in different clinical settings need to be established for the near future in order to avoid overtreatment and unnecessary cost expenditures for the health care system [47]. In metastatic bladder cancer, the standard first-line treatment is platinum-based multiagent chemotherapy. Patients who are not able to receive chemotherapy due to impaired performance status or renal function or do not show chemosensitivity exhibit poor overall survival. Therefore, anti-PD-L1 therapy represents an alternative treatment for
these patients. MPDL3280A is a high-affinity engineered human PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7-H1 (CD80). In particular, the Fc domain of MPDL3280A was modified to interrupt antibody-dependent cellular cytotoxicity, particularly in T-cells expressing PD-L1. In a phase I expansion study, it was shown that those tumors expressing PD-L1-positive tumor-infiltrating immune cells had notably improved response rates. In comparison to platin-based chemotherapy, this treatment option results in a much lower renal toxicity which gains relevance in older patients with UBC who suffer often from renal impairment. These results were granted as Bbreakthrough designation status^ by the US Food and Drug Administration (FDA) in June 2014 [48••].
Conclusions Checkpoint inhibitors against PD-1 and PD-L1 are promising targeted therapies to block the ability of tumors to circumvent the cytotoxic cellular response of the immune system. As PDL1 expression on bladder cancer cells correlates positively with tumor stage and grade patients with high-grade or advanced disease may profit most from treatment. As autoimmunological side effects may occur during treatment, there is a need to select appropriate patients who will benefit most. Furthermore, the combination of standard chemotherapeutic regimens with checkpoint inhibitors in different clinical settings needs to be defined in the near future in order to avoid overtreatment and unnecessary cost expenditures for health care system. Compliance with Ethics Guidelines
Conflict of Interest Johannes Mischinger, Eva Comperat, Christian Schwentner, Arnulf Stenzl, and Georgios Gakis each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Curr Urol Rep (2015) 16:59 48.•• Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62. This review describes the scientific rationale for the use of PD-L1 inhibitors in metastatic bladder cancer.
GENETICS AND MICROENVIRONMENT (X CATHELINEAU, SECTION EDITOR)
Inflammation and Cancer: What Can We Therapeutically Expect from Checkpoint Inhibitors? Johannes Mischinger 1 & Eva Comperat 2 & Christian Schwentner 1 & Arnulf Stenzl 1 & Georgios Gakis 1
# Springer Science+Business Media New York 2015
Abstract Programmed death-ligand 1 (PD-L1) is a cell surface protein which is mainly expressed on immune cells as well as on cancer cells and functions as a co-stimulatory molecule for T lymphocytes. It is capable of inducing apoptosis in T-cells via PD-1 which leads to impaired cytokine production and loss of cytotoxicity of activated T-cells. This represents a possible escape mechanism for cancer cells. Tumor infiltration by mononuclear cells and tumor aggressiveness was found to be associated with PD-L1 expression. In light of possible autoimmunological side effects, it remains currently unclear which patient will benefit most from this novel therapeutic approach. Furthermore, immunohistochemistry for PD-L1 has not been well standardized until now. In addition, the combination of chemotherapy with checkpoint inhibitors in different clinical settings needs to be established for the near future in order to avoid overtreatment and also unnecessary cost expenditures for the health care system.
Keywords Bladder cancer . Checkpoint inhibitor . Escape mechanism . PD-1 . PD-L1 . Prostate cancer
This article is part of the Topical Collection on Genetics and Microenvironment * Georgios Gakis [email protected] 1
Department of Urology, Eberhard-Karls University Tübingen, Hoppe-Seyler Strasse 3, 72076 Tübingen, Germany
2
Department of Pathology, Pitié-Salpêtrière Academic Hospital, Pierre and Marie Curie Medical School, Paris, France
Introduction In 2006, more than 1.7 million people died of cancer in Europe, while more than 3 million new cancer cases were diagnosed [1]. Until 2030, an increase from 14 to 21 million new cancer patients per year has been estimated with a trend towards increased mortality from 8 to 13 million people worldwide during this time period. Potential reasons for this development are multifactorial which include environmental and genetic factors as well as demographic changes especially in the Western countries with an excess in age and typical lifestyle [2]. Apart from these factors, more than 15 % of all malignancies can be related to infections, with about 1.2 million cases per year [3]. In the past, many different cancer entities have been associated with history of infection, i.e., gastric cancer (Helicobacter pylori), hepatocellular cancer (Hepatitis-B and -C virus), Kaposi-sarcoma/squamous-cell-carcinoma/nonHodgkin’s lymphoma (HIV), or Burkett’s lymphoma (Epstein-Barr virus) [4]. Cervical cancer is also attributed to viral infection but probably more due to the non- inflammatory oncogenic potential of HPV on cervical cells [5, 6]. In this regard, although distinct viruses have been found to be oncogenic which is supportive of the hypothesis that active oncogenes can be integrated into the host’s genome, only a subset of infected individuals will develop a malignant tumor. Therefore, this pathway does not provide a comprehensive explanation for inflammation-based cancer development and suggests the presence of other inflammation-mechanisms responsible for carcinogenesis [4]. Usually, chronic inflammation induces a rise of leucocytes and phagocytic cells which produce reactive oxygen and nitrogen substrates that exert cytotoxic properties. These two types can react to peroxynitrite which is a mutagenic agent that causes DNA damage in proliferating cells [7].
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In chronic inflammation, permanent tissue damage and restoration processes in the presence of peroxynitrite can lead to point mutations, deletions, or gene rearrangements [8•]. As an example, p53 mutations are found not only in tumors but also in tissues of chronic inflammatory disease, such as chronic inflammatory bowel disease or rheumatoid arthritis [9]. Furthermore, a constant secretion of macrophage migration inhibitory factor (MIF) by T lymphocytes and macrophages results in increased damage of the DNA. MIF is a cytokine that is capable of suppressing the transcriptional activity of p53. Permanent suppression of the function of the p53 gene in tumorinfiltrated tissue leads to excessive proliferation and cell viability. This results in a deficient host’s response to DNA damage and increased number of possible oncogenic mutations [10].
Inflammation and Prostate Cancer Prostate cancer represents the most frequent cancer entity in men with nearly 900,000 new cases and approximately 260, 000 deaths worldwide. The incidence is highest in Western countries [11]. Similarly to cervical cancer [12], there is evidence which suggests that prostate carcinogenesis can be related to viral infections. The human papillomavirus (HPV) has been detected in prostate cancer cells and perifocal tissue lesions [13]. Further investigations have shown no association between Chlamydia trachomatis, HPV-16 or HPV-33 seropositivity and prostate cancer development. Intriguingly, a significant inverse correlation between positive serum levels of anti-human herpesvirus 8 (HHV-8) antibody concentration and prostate carcinogenesis could be found [14]. In addition, the herpesvirus 2 could be detected in a subset of prostate cancer specimens after radical prostatectomy but patients with prostate cancer showed no higher levels of herpes simplex virus type 2 antibodies compared to patients with benign hypertrophy of the prostate [15]. In contrast, a positive serological status for Trichomonas vaginalis was positively associated with a higher risk for prostate cancer development as well as extraprostatic cancer growth and increased mortality [16]. Moreover, the Epstein-Barr virus was found in prostate cancer tissues, but not in healthy prostate specimens [17]. Inflammation of the prostate can also be caused by acute or chronic bacterial as well as abacterial infections which may result in chronic pelvic pain syndrome or subclinical inflammatory prostatitis [18]. Typical tissue characteristics related to prostatitis are commonly described in histopathological reports after surgical treatment of the prostate, i.e., prostate biopsy or transurethral resection of the prostate [19, 20]. A recent meta-analysis of 20 case-control studies reported a significantly increased risk for developing prostate cancer when
Curr Urol Rep (2015) 16:59
patients suffered from prostatitis in the past [21]. In older men, proliferative inflammatory atrophy (PIA) signifies large parts of the prostate which histologically corresponds to areas of prostatic atrophy due to inflammation and constitutes a risk factor for prostate cancer development. As a consequence of cellular damage, proliferating atrophic epithelial cells are regenerated and are capable of inducing prostatic intraepithelial neoplasia, a precursor lesion for prostate cancer [22].
Inflammation and Bladder Cancer In Western countries, bladder cancer represents the sixth most frequent cause for cancer death in men and the eight most common cause in women. In Germany, the incidence of bladder cancer in 2010 amounted to the fourth most common cancer in men and 14th most common malignancy in women. In the same year, it was the 10th most common cause for cancer death in men and 14th cause of death in women [23]. Non-muscle-invasive bladder cancer is characterized by a high recurrence and low progression rate [24]. As a consequence, treatment of bladder cancer induces the highest costs of all malignancies in Western health care systems [25]. As a result of improved bladder cancer management in the USA, a significant increase in 5-year survival rates has been observed for all urothelial tumor stages except for patients with metastatic disease [26]. In metastatic bladder cancer, effective tumor suppression necessitates an intact immune system [27, 4]. As an example, although invasive urothelial cancer cells have the ability to penetrate into the subepithelial tissue of the bladder, further invasion can be effectively prevented by intravesical instillation of Bacille CalmetteGuerin (BCG), an attenuated mycobacterium which induces bladder wall inflammation [28]. Although the exact pathway of bladder cancer cell invasion and formation of distant metastatic clones has not been sufficiently understood, an impaired immune response seems to be a requisite to any process of metastasis formation [29]. It has been consistently demonstrated for patients with invasive urothelial cancer that an increased preoperative level of C-reactive protein (CRP) is associated with inferior survival after radical surgery or first-line chemotherapy [30•, 31]. Immunohistochemical studies of patients treated with BCG for highgrade or early-invasive bladder cancer have shown that the relationship between the number of macrophages infiltrating into the cancer area and those in the tumor surrounding lamina propria is of prognostic value [32]. In this regard, macrophages can show a divergent way of immunologic action. There are two distinct types of macrophages with pro-inflammatory (type 1) and antiinflammatory (type 2) properties. In in vitro studies, cell viability of T24 cancer cells was found to be higher in T24 cell/macrophages-2 co-cultures compared to T24/
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macrophages-1 co-cultures. Interestingly, the inhibitory effect of macrophage-1-derived factors was suppressed by macrophage-2-derived factors while exogenous interleukin (IL)-10 reversed the effects of macrophage-1-derived factors [33]. An essential part of cellular immunity is constituted by CD4+- and CD8+-T-cells and natural killer cells (NKC). BCG is known to stimulate human peripheral blood mononuclear cells (PBMC) which lead to proliferation of effector cells which, in turn, exert a cytotoxic effect on bladder cancer cells. In this context, NKC and CD8(+) T-cells were found to be responsible for enhanced cytotoxicity induced by recombinant BCG-interferon (IFN)-alpha (rBCG-IFN-alpha). This enhanced effect is due to a higher capability of PBMC to secret interferon-gamma and interleukin (IL)-2. Conversely, the effect of rBCG-IFN-alpha could be reduced after application of neutralizing antibodies against IFN-alpha, IFN-gamma, and IL-2 [34]. Altogether, although the effects of immune cells on cancer cell apoptosis are not fully understood, macrophages seem to play a key role in the initiation of cancer cell apoptosis.
Escape Mechanisms of Urothelial Cancer Cells As for various other tumor entities, immunological escape mechanisms have also been described for bladder cancer. Distinct surface proteins on cancer cells have the ability to circumvent the cytotoxic cellular response of the immune system. Toll-like receptor 4 (TLR4) represents a member of the Toll-like receptor family which functions as a lipopolysaccharide (LPS) signaling receptor in urinary tract infections. An excessive release of LPS during septicemia (i.e., caused by an Escherichia coli infection) can enhance TLR4 signaling [35–37]. TLR4, originally found as an epitope on immune cells, has also been detected on tumor cells and is assumed to induce signaling pathways which protect tumor cells from the immune system [38]. Programmed death-ligand 1 (PD-L1) or B7-H1 is a cell surface protein which is mainly expressed on immune cells and functions as a co-stimulatory molecule for T lymphocytes. It is capable of inducing apoptosis in T-cells which leads to impaired cytokine production and loss of cytotoxicity of activated T-cells. This enables tumor cells to escape the cytotoxic effects of the immune system [39, 40]. Bladder cancer cells also show a high expression of TLR4 and PD-L1 on their cell surface. Activation of the TLR4 signaling pathway in bladder cancer cells upregulates PD-L1 expression which could be a potential target for inhibiting tumor escape mechanisms. This regulation is significantly suppressed by ERK (or JNK) inhibitors, which can restore sensitivity of T24 cells to cytotoxic T-cell (CTL)-mediated killing. These interactions represent a strategy for effective
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bladder cancer treatment. Interestingly in low-grade nonmuscle-invasive bladder cancer (NMIBC) cells, TLR4 expression is reduced compared to normal urothelial cells. The decline of TLR4 in patients with high-grade or muscleinvasive bladder cancer was even more pronounced. By contrast, patients with high-grade NMIBC exhibit significantly higher expression rates of PD-L1 and PD-1. Expression of PD-1 on tumor-infiltrating lymphocytes (TILs) and B7H1 on tumor cells showed a direct correlation [35]. Figure 1 outlines the interaction between cell surface proteins PD-1 and PD-L1 on lymphocytes and tumor cells. The expression of PD-L1 correlates positively with tumor stage. Among 280 high-risk bladder cancer cases, PD-L1 expression was found in 7 % of pTa tumors, 16 % of pT1, 23 % of pT2, 30 % of pT3/4, and even 45 % of patients with carcinoma in situ (CIS). In this context, tumor infiltration by mononuclear cells and tumor aggressiveness was associated with PD-L1 expression. Moreover, it was shown that patients who failed BCG therapy exhibited an extremely high density of B7-H1 within BCG granulomas which were found adjacent to the recurrent tumor tissue. The blockage of PD-L1 may also lead to an improvement of the host’s immune response especially in patients with BCG-refractory disease [41]. The effectiveness of this therapeutic approach could already be demonstrated in in vitro and in vivo tests. In a mice model for hepatocarcinoma, blockage of the PD-1/B7-H1 pathway with soluble PD-1 (sPD-1) expressed by an eukaryotic expression plasmid (pPD-1A) improved antitumor immunity. In addition, the secretion of IFN-gamma and TNF-alpha by lymphocytes was upregulated by sPD-1 blockade [42]. In 65 bladder cancer patients, B7-H1 expression was also significantly associated with a higher risk of postoperative tumor recurrence and inferior survival suggesting that the tumorassociated B7-H1 expression is an important prognostic factor in advanced tumor stages [43]. A recent study of 160 patients investigated the prognostic impact of PD-L1 expression in urothelial carcinoma (UC). PD-L1 positivity was evaluated using a mouse monoclonal anti-PD-L1 antibody on tumor cells (defined as ≥5 % staining of the tumor cell membrane) as well as on tumor-infiltrating mononuclear cells (TIMCs) and was correlated with clinical and pathological tumor
Fig. 1 Negative stimulatory effect of a cancer cell expressing PD-L1 on a T lymphocyte after binding to the major histocompatibility complex and its antigen on the T-cell receptor. Immune escape is mediated by simultaneous binding of PD-L1 to PD-1. Ag antigen, MHC major histocompatibility complex, PD-L1 programmed death-ligand 1, PD-1 programmed death-1, TCR T-cell receptor)
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characteristics. Only 20 % of the patients showed a positive PD-L1 expression on tumor cell membranes. Of 143 samples in which TIMCs could be verified, 40 % had positive PD-L1 expression on TIMCs. Interestingly, neither a history of smoking nor prior BCG therapy correlated with PD-L1 expression on tumor cells and TIMCs. In addition, there was no difference between PD-L1 positivity between non-invasive or invasive UC. In patients who developed metastases (M1) and were treated with systemic therapy, PD-L1 positivity on tumor cells could not be associated with overall survival (OS). By contrast, in patients with metastatic disease and positive PD-L1 expression on TIMCs, PD-L1 expression was an independent predictor of improved overall survival [44]. Notwithstanding, the PD-L1/PD-1 axis as a checkpoint for restoration of host immunity against tumor escape mechanisms has become a promising step towards durable remission in metastatic bladder cancer. Beneficial therapeutic effects have been already shown for various tumor entities, i.e., melanoma, lung and renal cancer. In light of possible autoimmunological side effects, it remains nowadays unclear which tumor patient will benefit most from this therapeutic approach. Furthermore, immunohistochemistry (IHC) for B7-H1 has not been well standardized, particularly due to the use of different antibodies and tissue preparation techniques, cut-off values, different clinical settings (primary vs. metastatic), and staining of tumor vs. immune cells. Patients with overexpression of B7-H1 showed improved clinical outcomes with anti-PD-1-directed therapy. However, since even patients with low expression levels of B7-H1 have also shown satisfactory clinical response rates to treatment, further research is necessary to better understand the role of the host’s immunological status on treatment response [45]. For patients with melanoma, renal cell carcinoma, and lung cancer, recent studies have shown that anti-PD-L1 and antiPD-1 therapies lead to significant response rates, even after multiple prior systemic therapies. Currently, anti-PD-1/PD-L1 antibodies, such as pembrolizumab and nivolumab, have been approved for the treatment of patients with metastatic melanoma. Furthermore, these two agents as well as diverse other anti-PD-1/L1 antibodies are also examined within clinical trials for the treatment of other solid malignancies such as bladder, lung, breast, and renal cancer [46]. In this regard, possible sequential therapeutical approaches of chemotherapy and immunotherapy in different clinical settings need to be established for the near future in order to avoid overtreatment and unnecessary cost expenditures for the health care system [47]. In metastatic bladder cancer, the standard first-line treatment is platinum-based multiagent chemotherapy. Patients who are not able to receive chemotherapy due to impaired performance status or renal function or do not show chemosensitivity exhibit poor overall survival. Therefore, anti-PD-L1 therapy represents an alternative treatment for
these patients. MPDL3280A is a high-affinity engineered human PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7-H1 (CD80). In particular, the Fc domain of MPDL3280A was modified to interrupt antibody-dependent cellular cytotoxicity, particularly in T-cells expressing PD-L1. In a phase I expansion study, it was shown that those tumors expressing PD-L1-positive tumor-infiltrating immune cells had notably improved response rates. In comparison to platin-based chemotherapy, this treatment option results in a much lower renal toxicity which gains relevance in older patients with UBC who suffer often from renal impairment. These results were granted as Bbreakthrough designation status^ by the US Food and Drug Administration (FDA) in June 2014 [48••].
Conclusions Checkpoint inhibitors against PD-1 and PD-L1 are promising targeted therapies to block the ability of tumors to circumvent the cytotoxic cellular response of the immune system. As PDL1 expression on bladder cancer cells correlates positively with tumor stage and grade patients with high-grade or advanced disease may profit most from treatment. As autoimmunological side effects may occur during treatment, there is a need to select appropriate patients who will benefit most. Furthermore, the combination of standard chemotherapeutic regimens with checkpoint inhibitors in different clinical settings needs to be defined in the near future in order to avoid overtreatment and unnecessary cost expenditures for health care system. Compliance with Ethics Guidelines
Conflict of Interest Johannes Mischinger, Eva Comperat, Christian Schwentner, Arnulf Stenzl, and Georgios Gakis each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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