The application of Toll like receptors for cancer therapy

So, Eui Young; Ouchi, Toru

doi:10.7150/ijbs.6.675

Cited by 127 publications

(118 citation statements)

References 54 publications

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“…Furthermore, strong interactions between cancerous IgGs and toll-like recaptors (TLRs) in the innate immunity of cancer cells were observed through extensive gene regulation studies [28]. These experimental observations seem to suggest that cancerous antigen receptors may play undefined roles in the innate immune system, similar to those of TLRs in cancer cells [29].…”

Section: Introductionmentioning

confidence: 82%

“…Currently, the exact mechanism by which cancerous immunoglobulins alter TLR gene expression and cause upregulation of NFκB in cancer cells remains to be elucidated. However, both TLRs and cancerous immunoglobulins have been shown to be required for the growth and survival of cancer cells [19,[72][73][74][75][76]. Therefore, the expressions of antigen receptors and TLRs in cancer cells may be due to their protective roles in the innate immune system of cancer cells for cancer cell growth and survival.…”

Section: Possible Roles Of Cancerous Immunoglobulins and Toll-like Rementioning

confidence: 99%

“…Furthermore, treatment of OC-3-VGH ovarian cancer cells and C-33A cervical cancer cells with RP215 or anti-antigen receptor antibodies resulted in upregulation of NFκB, which is also activated by the TLR signalling cascade [28]. NFκB is known to be a significant transcription factor involved in the gene regulations/expression of both antigen receptors and TLRs, as well as more than 200 other genes in a variety of biological functions in different cell types [29,[49][50][51][68][69][70][71]. Currently, the exact mechanism by which cancerous immunoglobulins alter TLR gene expression and cause upregulation of NFκB in cancer cells remains to be elucidated.…”

Section: Possible Roles Of Cancerous Immunoglobulins and Toll-like Rementioning

confidence: 99%

“…These cancerous TLRs are believed to promote both tumor growth and immune evasion through upregulation of NFκB and production of anti-apoptotic molecules [29,60,61]. A variety of cancer cells and cancer cell lines have been shown to express functionally active TLRs, such as TLR-2, -3, -4, and -5 in ovarian cancer [29,61,62], TLR-3, -4, -5, and -9 in cervical cancer [61,[63][64][65], TLR-9 in lung cancer [43], TLR-4, -5, -9 in gastric cancer [66], and TLR-2, -3, and -4 in colorectal cancer cells lines [67]. In general, TLR-4 and TLR-9 was found to be most strongly expressed in human cancer cells [32].…”

Section: Effects Of Rp215 Anti-human Immunoglobulin G and Anti-t Cementioning

confidence: 99%

“…Therefore, the effects of anti-antigen receptor antibodies and RP215 on the gene regulations of TLRs, which are essential elements of the innate immune system in cancer cells, were examined. TLRs are known to belong to the family of pattern-recognition receptors (PPRs) which recognize microbe-associated molecular patterns (MAMPs), and play important roles in innate immunity [29,[48][49][50][51]. In addition, TLRs are also involved in carcinogenesis and in the growth/proliferation of cancer cells [52][53][54][55][56][57][58][59].…”

Section: Effects Of Rp215 Anti-human Immunoglobulin G and Anti-t Cementioning

confidence: 99%

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Roles of antigen receptors and CA215 in the innate immunity of cancer cells

Lee¹,

Liu²

2013

OJI

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Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that cancerous immunoglobulins play significant roles in the growth and proliferation of cancer cells in vitro and in vivo. RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. Through gene regulation studies, both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell proliferation (such as NFκB-1, IgG, P21, cyclin D1, ribosomal P 1 , and c-fos). Furthermore, selected toll-like receptor genes (TLR-2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and antiantigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and downregulate TLR-4 and TLR-9 in two types of cancer cells. Based on these studies, it is reasonable to postulate that cancerous immunoglobulins play important roles in the modulation of the innate immune system to allow the growth and survival of cancer cells within the human body. Consequently, RP215 in its humanized forms may be utilized to target cancer cells for potential therapeutic purposes.

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Section: Introductionmentioning

confidence: 82%

Section: Possible Roles Of Cancerous Immunoglobulins and Toll-like Rementioning

confidence: 99%

Section: Possible Roles Of Cancerous Immunoglobulins and Toll-like Rementioning

confidence: 99%

Section: Effects Of Rp215 Anti-human Immunoglobulin G and Anti-t Cementioning

confidence: 99%

Section: Effects Of Rp215 Anti-human Immunoglobulin G and Anti-t Cementioning

confidence: 99%

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Roles of antigen receptors and CA215 in the innate immunity of cancer cells

Lee¹,

Liu²

2013

OJI

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The immunostimulatory effects and pro‐apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll‐like receptor 4

et al. 2019

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Background Recombinant human calcineurin B subunit (rhCNB) has been shown to be an immune‐stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll‐like receptor 4 (TLR4) complex, but it was not known whether its immuno‐modulatory and antitumor functions involved entry by this same route. Methods The production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild‐type (WT) mice, TLR4 −/− mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively. Results Recombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB‐stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up‐regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4 + cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4 + and CD8 + T cells in splenocytes from WT mice, but not from TLR4‐deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4 −/− littermates. Conclusions The in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug.

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Novel immunotherapeutic options for BCG‐unresponsive high‐risk non‐muscle‐invasive bladder cancer

Hannouneh,

Hijazi,

Alsaleem

et al. 2023

Cancer Medicine

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BackgroundHigh‐risk non‐muscle‐invasive bladder cancer (HR‐NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette–Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle‐invasive bladder cancer (MIBC). Patients who are BCG‐unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.MethodsTo address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR‐NMIBC treated with immune‐related agents were retrieved from clinicaltrials.gov.Findings and Future PerspectivesExploratory treatments for BCG‐Unresponsive HR‐NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs—pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec‐vncg—have been FDA approved for the treatment of BCG‐unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long‐term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR‐NMIBC is essential for the discovery of new targets and the development of effective treatments.

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The application of Toll like receptors for cancer therapy

Cited by 127 publications

References 54 publications

Roles of antigen receptors and CA215 in the innate immunity of cancer cells

Roles of antigen receptors and CA215 in the innate immunity of cancer cells

The immunostimulatory effects and pro‐apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll‐like receptor 4

Novel immunotherapeutic options for BCG‐unresponsive high‐risk non‐muscle‐invasive bladder cancer

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