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Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy

Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy Hindawi Journal of Oncology Volume 2018, Article ID 8653489, 7 pages https://doi.org/10.1155/2018/8653489 Review Article Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy Maiko Matsushita and Mai Kawaguchi Division of Clinical Physiology and erapeutics, Keio University, Faculty of Pharmacy, --, Shiabakoen, Minato-Ku, Tokyo, Japan Correspondence should be addressed to Maiko Matsushita; matsushita-mk@pha.keio.ac.jp Received 31 August 2018; Accepted 10 October 2018; Published 25 October 2018 Guest Editor: Hailun Wang Copyright © 2018 Maiko Matsushita and Mai Kawaguchi. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Recent advances in cancer immunotherapy, including immune checkpoint inhibitors or adoptive T cell therapies, have contributed to better outcomes in cancer patients. However, there are still many cancers with no cure. Therefore, combinations of several treatment strategies are being explored, and enhancing anticancer immunity will play an important role to combat the disease. eTh re have been several reports on the immune-modulatory effects of commonly used drugs, namely, statin, metformin, and angiotensin receptor blockers (ARBs), which suggest that these drugs could enhance immunity against cancer cells. Other anticancer drugs, such as anthracyclines, thalidomides, lenalidomides, and hypomethylating drugs, could also strengthen the immune system to attack cancer cells at a relatively low dose. Hence, these drugs might contribute to better outcomes in cancer patients. 1. Introduction drugs [12, 13]. In this review, we discuss drugs that have been reported to elicit immunomodulatory effects in addition to Immune system dysfunction is related to many diseases, their original pharmacological effects. including inflammatory diseases, autoimmune diseases, We searched previously published literature for pa- infectious diseases, atherosclerosis, and cancer [1–5]. Several pers on immunomodulatory function of drugs using drugs that directly target the immune system have been PubMed (https://www.ncbi.nlm.nih.gov/pubmed/). By using developed for the treatment of these disorders. For example, “immunomodulating” and “drugs” as search words, we immune checkpoint inhibitors (ICIs) have greatly improved obtained 3433 papers (August 2018). We excluded papers the outcome of various cancers by altering patients’ immune- with monoclonal antibodies and previously approved im- suppressive status and enhancing antitumor immunity [6– munosuppressive drugs, such as corticosteroids. We classified 8]. However, even ICIs are ineffective in the treatment and the remaining drugs, obtained in the search, based on their cure of certain cancers. Therefore, new strategies to enhance effects on cytokines (Table 1), immune cells (T cells, B the efficacy of these treatments are needed. Moreover, ICIs cells, and antigen presenting cells; Table 2), and immune- and many of the other targeted anticancer therapies consist of related signaling pathways (nuclear factor-kappa B: NF-kB, monoclonal antibodies, which make them highly expensive. Signal Transducers and Activator of Transcription: STAT, On the other hand, immunomodulatory effects have Peroxisome Proliferator-Activated Receptor 𝛾 :PPAR1𝛾 , been described for several small molecular drugs, which Extracellular Signal-Regulated Kinase: ERK, mechanistic have been used for a long time to treat common diseases, target of rapamycin: mTOR, and AMP-activated protein including hyperlipidemia, diabetes, and hypertension [9–11]. kinase: AMPK; Table 3). These drugs are cost-eeff ctive and could be used safely, as their adverse reactions are well known. If immunomodula- To ascertain drugs that could be used for cancer treat- ment, we selected the drugs that have been reported to have tory effects of these previously approved drugs are clearly established, it might be possible to enhance the eeff cts of anticancer effects by enhancing immunological responses to cancer cells. Three drugs approved for treatment of conventional cancer therapy by combinatorial use of these 2 Journal of Oncology ff fl Table 1: Eects on cytokine productions by commonly used drugs. IL-1 IL-6 IL-8 TNF- IFN- IL-2 IL-4 IL-12 IL-18 TNF- IL-3 IL-5 IL-10 IL-13 H2 receptor antagonist NSAIDs Prostaglandin Noroxacin ↓↓ ↑ Linezolid ↓↓ ↓↓↓ ↑ Macrolide ↓↓or↑ ↑↓↓ ↓or↑↓or↑↓or↑↓or↑ Antifungal ↑↑ ↑ ↓↓ drugs 2adrenalin agonist D2 receptor agonist ACE inhibitor ↓ ARB ↓↓ Ca channel ↓or↑↓or↑ ↓↓↑ blocker Digoxin DPP4 inhibitor GLP-1 receptor ↓↓ agonist Biguanide Statin ↓ Journal of Oncology 3 Table 2: Eeff cts on immune cells by commonly used drugs. T celll Th1 Treg Th17 MDSC CTL B cell NK CD4 CD8+TIL H2 receptor antagonist NSAIDs ↑ Prostaglandin Norfloxacin Linezolid Macrolide ↑ Antifungal drugs 𝛽 2adrenalin agonist D2 receptor agonist ACE inhibitor ↓ ARB ↓ Ca channel blocker Digoxin ↓ DPP4 inhibitor ↑↓ Biguanide ↑ Statin ↓ ↓↑↓ ↓ Table 3: Eeff cts on gene expressions in immune-related signaling pathways by commonly used drugs. NF-𝜅BSTAT PPAR1𝛾 ERK mTOR AMPK H2 receptor antagonist NSAIDs Prostaglandin Norfloxacin Linezolid ↓ Macrolide ↓↓ Antifungal drugs 𝛽 2adrenalin agonist D2 receptor agonist ACE inhibitor ARB Ca channel ↓or↑ blocker Digoxin DPP4 inhibitor ↑ Biguanide ↓↑ Statin ↓↑ ↑ Cannabidiol 4 Journal of Oncology common diseases (statin, metformin, and angiotensin recep- angiotensin, which play a pathophysiological role in cancer tor blocker) and three categories of anticancer drugs development [32]. Several clinical studies have demonstrated that show immunomodulatory effects (thalidomide and its that taking ARBs could decrease the risk of developing derivatives, anthracyclines or other chemotherapeutic drugs, cancers [33, 34]. In vitro and in vivo studies have further and demethylating agents) are discussed further for their revealed that these anticancer effects of ARB include direct anticancer property via immunological mechanisms. suppression of cancer growth and increase of antitumor immunity [35–38]. Nakamura et al. showed that adminis- tration of ARB to colon cancer-bearing mice induced the 2. Immunomodulatory Effects of Drugs Used expansion of cancer-specific CTLs and reduced the levels of for Treating Common Diseases immune-suppressive cytokines, interleukin-6 (IL-6), IL-10, vascular endothelial cell factor, and arginase in the tumor .. Statins. Statins have been used by millions of peo- microenvironment [39]. They demonstrated that combina- ple for lowering blood lipids to prevent coronary heart tion therapy with ARB and anti PD-L1 antibody significantly disease [14]. They inhibit hydroxymethylglutaryl (HMG) reduced tumor size, suggesting that this therapy is also useful CoA reductase in the cholesterol biosynthesis pathway. In in clinical setting. addition to their cholesterol-lowering effects, many studies have shown that statins also exhibit immune-modulatory properties through mevalonate-independent and -dependent 3. Immunomodulating Effects of pathways [15]. They inhibit the activity of Ras and Rho family Anticancer Drugs GTPases, which regulate various cellular functions, such as cell death, metastasis, and immune reactions [16–18]. Statins .. alidomide, Lenalidomide, and Pomalidomide. Thalido- aec ff t the immune cells by decreasing the production of mide, and its derivatives, lenalidomide, and pomalidomide inflammatory cytokines and activating CD8 Tcells [19]. are used as key drugs in the treatment of multiple myeloma, Sarrabayrouse et al. have also reported that statin treatment which is a plasma cell neoplasm [40–42]. Thalidomide first induces the expression of CD80 and CD86 in melanoma cells made headlines for its direct tumoricidal effects on myeloma by upregulating their gene expression through transcriptional cells by causing cell cycle arrest and also its antiangiogenic factors controlled by Rho proteins [20]. In fact, clinical properties. Later, it was classified as an immunomodula- studies have confirmed the role of statins in preventing tory drug (IMiD) owing to its immunological effects [43]. several types of cancer [21–23]. These data suggest that statins IMiDs stimulate T cells and natural killer T (NKT) cells to might be useful for enhancing the immunity against cancer secrete IL-2 and interferon-𝛾 , leading to NK cell activation cells. and inhibition of regulatory T cells. As a result, myeloma- specicfi immunity is ampliefi d [44–46]. The FDA has recently approved lenalidomide for maintenance therapy of posttrans- .. Metformin. Metformin is one of the widely used antidi- plant myeloma patients, considering that lenalidomide can abetic drugs synthesized from the plant Galega officinalis, suppress the residual myeloma cells. which lowers blood glucose level by suppressing hepatic glucose production in patients with type 2 diabetes [24]. It inhibits NADH: ubiquinone oxidoreductase located in .. Anthracyclines and Other Chemotherapeutic Drugs. the mitochondrial membrane, leading to the activation of Some of conventional anticancer drugs, such as anthracy- 5 -AMP-activated protein kinase (AMPK) and suppression clines or alkylating agents, have been reported to cause of gluconeogenesis. AMPK-independent pathway also con- induction of immunomodulatory effects on various cancer tributes to its pharmacological actions [25]. In addition to cells by enhancing the cell surface expression of calreticulin its antihyperglycemic effects, there are many reports of its (CRT) followed by the release of high mobility group box role in immune response. It has been shown that metformin 1(HMGB1),ATP,annexin A1, and typeI interferon from enhances the number and function of tumor-infiltrating cancer cells [47–50]. The dendritic cells (DCs) then recognize lymphocytes (TILs) [26]. Pereira et al. have reported that CRT, HMGB1, and ATP through CD91, Toll-like receptor metformin exerts strong immunomodulatory eeff cts and 4, and P2X purinoreceptor 7, respectively, and take up the contributes to reduced lung metastasis of melanoma cells cancer cells. This series of events is called immunogenic [27]. Cha et al. have shown that metformin reduces the cell death (ICD) [51–53]. Mouse immunization experiments stability and membrane localization of programmed death- using cancer cells pretreated with chemotherapeutic drugs, ligand 1 (PD-L1) and contributes to the enhancement of such as doxorubicin or mitoxantrone, have shown eeff ctive cytotoxic T lymphocyte (CTL) activity against cancer cells cancer regression through CRT expression and HMGB1 [28]. Metformin also exerts anti-inflammatory effects [29, secretion [54–56]. These observations were further con- 30]. It was recently reported that these effects might be related firmed by clinical data, which have indicated that CRT to the alteration of gut microbiota [31]. These results suggest expression is important for the improvement of disease that metformin can be used for the treatment of cancer. outcome in cancer patients [57]. These results suggest that some of the chemotherapeutic drugs not only kill cancer .. Angiotensin Receptor Blockers (ARBs). Renin-angiotens- cells directly but also strengthen patients’ immune reactions in system mainly controls blood pressure; however, cancer against cancer cells, thereby contributing to the eradication cells and their microenvironment also express renin and of cancer cells. 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Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy

Matsushita, Maiko; Kawaguchi, Mai
Journal of Oncology , Volume 2018: 7 – Oct 25, 2018
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Hindawi Publishing Corporation
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Copyright © 2018 Maiko Matsushita and Mai Kawaguchi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2018/8653489
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Abstract

Hindawi Journal of Oncology Volume 2018, Article ID 8653489, 7 pages https://doi.org/10.1155/2018/8653489 Review Article Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy Maiko Matsushita and Mai Kawaguchi Division of Clinical Physiology and erapeutics, Keio University, Faculty of Pharmacy, --, Shiabakoen, Minato-Ku, Tokyo, Japan Correspondence should be addressed to Maiko Matsushita; matsushita-mk@pha.keio.ac.jp Received 31 August 2018; Accepted 10 October 2018; Published 25 October 2018 Guest Editor: Hailun Wang Copyright © 2018 Maiko Matsushita and Mai Kawaguchi. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Recent advances in cancer immunotherapy, including immune checkpoint inhibitors or adoptive T cell therapies, have contributed to better outcomes in cancer patients. However, there are still many cancers with no cure. Therefore, combinations of several treatment strategies are being explored, and enhancing anticancer immunity will play an important role to combat the disease. eTh re have been several reports on the immune-modulatory effects of commonly used drugs, namely, statin, metformin, and angiotensin receptor blockers (ARBs), which suggest that these drugs could enhance immunity against cancer cells. Other anticancer drugs, such as anthracyclines, thalidomides, lenalidomides, and hypomethylating drugs, could also strengthen the immune system to attack cancer cells at a relatively low dose. Hence, these drugs might contribute to better outcomes in cancer patients. 1. Introduction drugs [12, 13]. In this review, we discuss drugs that have been reported to elicit immunomodulatory effects in addition to Immune system dysfunction is related to many diseases, their original pharmacological effects. including inflammatory diseases, autoimmune diseases, We searched previously published literature for pa- infectious diseases, atherosclerosis, and cancer [1–5]. Several pers on immunomodulatory function of drugs using drugs that directly target the immune system have been PubMed (https://www.ncbi.nlm.nih.gov/pubmed/). By using developed for the treatment of these disorders. For example, “immunomodulating” and “drugs” as search words, we immune checkpoint inhibitors (ICIs) have greatly improved obtained 3433 papers (August 2018). We excluded papers the outcome of various cancers by altering patients’ immune- with monoclonal antibodies and previously approved im- suppressive status and enhancing antitumor immunity [6– munosuppressive drugs, such as corticosteroids. We classified 8]. However, even ICIs are ineffective in the treatment and the remaining drugs, obtained in the search, based on their cure of certain cancers. Therefore, new strategies to enhance effects on cytokines (Table 1), immune cells (T cells, B the efficacy of these treatments are needed. Moreover, ICIs cells, and antigen presenting cells; Table 2), and immune- and many of the other targeted anticancer therapies consist of related signaling pathways (nuclear factor-kappa B: NF-kB, monoclonal antibodies, which make them highly expensive. Signal Transducers and Activator of Transcription: STAT, On the other hand, immunomodulatory effects have Peroxisome Proliferator-Activated Receptor 𝛾 :PPAR1𝛾 , been described for several small molecular drugs, which Extracellular Signal-Regulated Kinase: ERK, mechanistic have been used for a long time to treat common diseases, target of rapamycin: mTOR, and AMP-activated protein including hyperlipidemia, diabetes, and hypertension [9–11]. kinase: AMPK; Table 3). These drugs are cost-eeff ctive and could be used safely, as their adverse reactions are well known. If immunomodula- To ascertain drugs that could be used for cancer treat- ment, we selected the drugs that have been reported to have tory effects of these previously approved drugs are clearly established, it might be possible to enhance the eeff cts of anticancer effects by enhancing immunological responses to cancer cells. Three drugs approved for treatment of conventional cancer therapy by combinatorial use of these 2 Journal of Oncology ff fl Table 1: Eects on cytokine productions by commonly used drugs. IL-1 IL-6 IL-8 TNF- IFN- IL-2 IL-4 IL-12 IL-18 TNF- IL-3 IL-5 IL-10 IL-13 H2 receptor antagonist NSAIDs Prostaglandin Noroxacin ↓↓ ↑ Linezolid ↓↓ ↓↓↓ ↑ Macrolide ↓↓or↑ ↑↓↓ ↓or↑↓or↑↓or↑↓or↑ Antifungal ↑↑ ↑ ↓↓ drugs 2adrenalin agonist D2 receptor agonist ACE inhibitor ↓ ARB ↓↓ Ca channel ↓or↑↓or↑ ↓↓↑ blocker Digoxin DPP4 inhibitor GLP-1 receptor ↓↓ agonist Biguanide Statin ↓ Journal of Oncology 3 Table 2: Eeff cts on immune cells by commonly used drugs. T celll Th1 Treg Th17 MDSC CTL B cell NK CD4 CD8+TIL H2 receptor antagonist NSAIDs ↑ Prostaglandin Norfloxacin Linezolid Macrolide ↑ Antifungal drugs 𝛽 2adrenalin agonist D2 receptor agonist ACE inhibitor ↓ ARB ↓ Ca channel blocker Digoxin ↓ DPP4 inhibitor ↑↓ Biguanide ↑ Statin ↓ ↓↑↓ ↓ Table 3: Eeff cts on gene expressions in immune-related signaling pathways by commonly used drugs. NF-𝜅BSTAT PPAR1𝛾 ERK mTOR AMPK H2 receptor antagonist NSAIDs Prostaglandin Norfloxacin Linezolid ↓ Macrolide ↓↓ Antifungal drugs 𝛽 2adrenalin agonist D2 receptor agonist ACE inhibitor ARB Ca channel ↓or↑ blocker Digoxin DPP4 inhibitor ↑ Biguanide ↓↑ Statin ↓↑ ↑ Cannabidiol 4 Journal of Oncology common diseases (statin, metformin, and angiotensin recep- angiotensin, which play a pathophysiological role in cancer tor blocker) and three categories of anticancer drugs development [32]. Several clinical studies have demonstrated that show immunomodulatory effects (thalidomide and its that taking ARBs could decrease the risk of developing derivatives, anthracyclines or other chemotherapeutic drugs, cancers [33, 34]. In vitro and in vivo studies have further and demethylating agents) are discussed further for their revealed that these anticancer effects of ARB include direct anticancer property via immunological mechanisms. suppression of cancer growth and increase of antitumor immunity [35–38]. Nakamura et al. showed that adminis- tration of ARB to colon cancer-bearing mice induced the 2. Immunomodulatory Effects of Drugs Used expansion of cancer-specific CTLs and reduced the levels of for Treating Common Diseases immune-suppressive cytokines, interleukin-6 (IL-6), IL-10, vascular endothelial cell factor, and arginase in the tumor .. Statins. Statins have been used by millions of peo- microenvironment [39]. They demonstrated that combina- ple for lowering blood lipids to prevent coronary heart tion therapy with ARB and anti PD-L1 antibody significantly disease [14]. They inhibit hydroxymethylglutaryl (HMG) reduced tumor size, suggesting that this therapy is also useful CoA reductase in the cholesterol biosynthesis pathway. In in clinical setting. addition to their cholesterol-lowering effects, many studies have shown that statins also exhibit immune-modulatory properties through mevalonate-independent and -dependent 3. Immunomodulating Effects of pathways [15]. They inhibit the activity of Ras and Rho family Anticancer Drugs GTPases, which regulate various cellular functions, such as cell death, metastasis, and immune reactions [16–18]. Statins .. alidomide, Lenalidomide, and Pomalidomide. Thalido- aec ff t the immune cells by decreasing the production of mide, and its derivatives, lenalidomide, and pomalidomide inflammatory cytokines and activating CD8 Tcells [19]. are used as key drugs in the treatment of multiple myeloma, Sarrabayrouse et al. have also reported that statin treatment which is a plasma cell neoplasm [40–42]. Thalidomide first induces the expression of CD80 and CD86 in melanoma cells made headlines for its direct tumoricidal effects on myeloma by upregulating their gene expression through transcriptional cells by causing cell cycle arrest and also its antiangiogenic factors controlled by Rho proteins [20]. In fact, clinical properties. Later, it was classified as an immunomodula- studies have confirmed the role of statins in preventing tory drug (IMiD) owing to its immunological effects [43]. several types of cancer [21–23]. These data suggest that statins IMiDs stimulate T cells and natural killer T (NKT) cells to might be useful for enhancing the immunity against cancer secrete IL-2 and interferon-𝛾 , leading to NK cell activation cells. and inhibition of regulatory T cells. As a result, myeloma- specicfi immunity is ampliefi d [44–46]. The FDA has recently approved lenalidomide for maintenance therapy of posttrans- .. Metformin. Metformin is one of the widely used antidi- plant myeloma patients, considering that lenalidomide can abetic drugs synthesized from the plant Galega officinalis, suppress the residual myeloma cells. which lowers blood glucose level by suppressing hepatic glucose production in patients with type 2 diabetes [24]. It inhibits NADH: ubiquinone oxidoreductase located in .. Anthracyclines and Other Chemotherapeutic Drugs. the mitochondrial membrane, leading to the activation of Some of conventional anticancer drugs, such as anthracy- 5 -AMP-activated protein kinase (AMPK) and suppression clines or alkylating agents, have been reported to cause of gluconeogenesis. AMPK-independent pathway also con- induction of immunomodulatory effects on various cancer tributes to its pharmacological actions [25]. In addition to cells by enhancing the cell surface expression of calreticulin its antihyperglycemic effects, there are many reports of its (CRT) followed by the release of high mobility group box role in immune response. It has been shown that metformin 1(HMGB1),ATP,annexin A1, and typeI interferon from enhances the number and function of tumor-infiltrating cancer cells [47–50]. The dendritic cells (DCs) then recognize lymphocytes (TILs) [26]. Pereira et al. have reported that CRT, HMGB1, and ATP through CD91, Toll-like receptor metformin exerts strong immunomodulatory eeff cts and 4, and P2X purinoreceptor 7, respectively, and take up the contributes to reduced lung metastasis of melanoma cells cancer cells. This series of events is called immunogenic [27]. Cha et al. have shown that metformin reduces the cell death (ICD) [51–53]. Mouse immunization experiments stability and membrane localization of programmed death- using cancer cells pretreated with chemotherapeutic drugs, ligand 1 (PD-L1) and contributes to the enhancement of such as doxorubicin or mitoxantrone, have shown eeff ctive cytotoxic T lymphocyte (CTL) activity against cancer cells cancer regression through CRT expression and HMGB1 [28]. Metformin also exerts anti-inflammatory effects [29, secretion [54–56]. These observations were further con- 30]. It was recently reported that these effects might be related firmed by clinical data, which have indicated that CRT to the alteration of gut microbiota [31]. These results suggest expression is important for the improvement of disease that metformin can be used for the treatment of cancer. outcome in cancer patients [57]. These results suggest that some of the chemotherapeutic drugs not only kill cancer .. Angiotensin Receptor Blockers (ARBs). Renin-angiotens- cells directly but also strengthen patients’ immune reactions in system mainly controls blood pressure; however, cancer against cancer cells, thereby contributing to the eradication cells and their microenvironment also express renin and of cancer cells. 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