Role of Pattern-Recognition Receptors (PRR)s in Cancer Progression
Prosjekt
- Prosjektnummer
- 90064600
- Ansvarlig person
- Nadra J. Nilsen
- Institusjon
- NTNU, CEMIR
- Prosjektkategori
- Forskerstipend
- Helsekategori
- Inflammatory and Immune System
- Forskningsaktivitet
- 1. Underpinning
Rapporter
The project has provided new insight into how ones innate immune defenses and inflammation affects cancer progression. The results emphasize important consequences of activating innate immunity in the tumor microenvironment (TM), which has implications for cancer immunotherapy. The project has centered on the role of a family of innate immune receptors termed Pattern Recognition Receptors (PRR)s and how inflammatory responses mediated by these receptors affect cancer progression.
PRRs are highly expressed on innate immune cells and are important for initiating responses that trigger anti-cancer immunity, but may also drive chronic inflammation that fuels cancer progression when deregulated. In this project we have studied the cancers multiple myeloma (MM) and colorectal cancer (CRC), since inflammatory responses play important roles in the progression of these cancers. We have concentrated on assessing the role of the signaling PRRs; Toll-Like Receptors (TLR)s. We were particularly interested in the role of TLRs 3,7 and 9, since these are promising targets in cancer immunotherapy due to the potent type I interferon (IFN) immune responses they induce.
In this project we have found that cancer cells also can express TLRs, but these cells may display altered TLR expression and signaling. TLR activation in these cells and can promote cancer progression rather than impair it. In colon cancer cells we found altered TLR3 expression and signaling promoted the invasiveness of cancerous intestinal epithelial cells (IEC)s, rather than inducing cell death. Several chemokines and proteases associated with migration and invasion are upregulated in a TLR3-dependent manner in cancer cells. Many of these molecules are also upregulated in tissue biopsies from CRC patients. TLR3 activators are currently being tested in clinical trials to enhance cancer therapy. Our results imply that TLR3 activation in the TM should be carefully targeted to avoid deterimental effects of TLR3 activation in cancer cells. The project has also looked further into TLR3 activation in colon cancer cells and studied the mechanism of how TLR-triggered responses can promote the invasiveness of these cells. In future projects we aim to determine how deterimental effects of TLR3 activation in cancer cells can be avoided.
We have also observed a high neutrophil/lymphocyte ratio in tumor tissue compared to healthy tissue. This is a characteristic that is frequently observed in several cancer types.The role of neutrophils in the tumor are still poorly understood, but it is becoming clear that these cells can have pivotal effects on tumor progression depending on their polarization state. We have established a model to study human neutrophil polarization. Using this model we have gained insight into the characteristics of subsets of neutrophils. We have also observed that TLR3 activation of cancer cells can induce neutrophil recruitment and trigger the polarization of these cells. In future projects we aim to further investigate how neutrophil subsets affect cancer progression and how TLRs can be applied to skew neutrophil polarization to impair cancer progression.
In MM we have found that MM cells release TLR activating components which trigger inflammatory responses in the tumor microenvironment and fuel cancer cell survival. We have observed that stromal cells respond to MM-conditioned medium in a TLR-dependent manner which induces cytokine production in these cells that in turn promotes MM survival. This indicates that MM cells can release TLR activators to trigger responses in the tumor microenvironment that facilitate cancer progression. We are currently identifying the nature of the TLR activators in MM CM and designing approaches to block these MM driven TLR responses in the TM.
The project has provided new insight into the role of innate immunity in cancer progression. This has implications for cancer immunotherapy since innate immunity initiates and shapes the adaptive immune responses that drive the efficacy of cancer therapy. Our results emphasize that cancer cells can diplay altered expresion of immune receptors and trigger immune responses in the tumor microenvironment that promote their survival and invasiveness. We also highlight the importance of innate immune cells in the tumor microenvironment that may affect cancer cell survival and the efficacy of cancer immunotherapy. The results provide a basis for targeting innate immune responses more precisely in approaches aiming to enhance cancer immunotherapy. Understanding the interplay between cancer cells and immune cells in the tumor microenvironment can help to identify new targets for improving cancer immunotherapy and thereby benefit cancer patients. We are currently investigating several approaches aiming to target innate immunity and innate immune responses in cancer therapy.
We aim to determine how ones immune defense and inflammation affects cancer progression, and how these can be targeted efficiently in immunotherapy. The project centers on the role of a family of innate immune receptors termed Pattern Recognition Receptors (PRR)s and how inflammatory responses mediated by these receptors affect cancer progression.PRRs are highly expressed on innate immune cells and are important for initiating responses that trigger anti-cancer immunity, but may also drive chronic inflammation that fuels cancer progression and autoimmune disease when deregulated. We are currently studying the cancers multiple myeloma (MM) and colorectal cancer (CRC), since inflammatory responses play important roles in the progression of these cancers. We have concentrated on assessing the role of the signaling PRRs; Toll-Like Receptors (TLR)s. We are particularly interested in the role of TLRs 3,7 and 9 in cancer progression, since these are promising targets in cancer immunotherapy due to the potent type I interferon (IFN) immune responses they induce. These TLRs recognize nucleic acids associated with viral infection, or released from injured cells.
This year we have focused mainly on the role of TLR3 in CRC. We have previously published that altered TLR3 expression and signaling drives the invasiveness of cancerous intestinal epithelial cells (IEC)s, rather than inducing anti-tumor immunity. We have found that chemokines and proteases associated with migration and invasion are upregulated in a TLR3-dependent manner. Many of the same molecules are upregulated in tissue biopsies from CRC patients. We also see a high neutrophil/lymphocyte ratio in tumor tissue compared to healthy tissue, which is a characteristic that is frequently observed in several cancer types. In vitro, we have observed that TLR3 activation of cancer cells induces neutrophil recruitment. The role of neutrophils in the tumor are still poorly understood, but it is becoming clear that these cells can have pivotal effects on tumor progression depending on their polarization state. Neutrophils with N1 characteristics generally impair tumor progression, while neutrophils with N2 characteristics may promote tumor growth by promoting a immunosuppressive environment. We have established a model to study human N1 and N2 neutrophils. Using this model we have gained insight into the characteristics of these subsets of neutrophils. We have also observed that TLR3 activation of cancer cells can drive the polarization of these cells. Our results imply that TLR3 activation in the tumor can both promote neutrophil recruitment and polarization of neutrophils and we are now looking into how this may affect the survival and proliferation of cancer cells.
In MM we have mainly focused on how MM cells release TLR activating components which trigger inflammatory responses in the tumor microenvironment that may potentially fuel tumor progression. We have previously identified that some MM cells release components that activate TLR8. We have now observed that MM cells can also release components that activate TLR9. Our results show that MM cells and other cells in the tumor microenvironment express these TLRs. These TLR-activating components induce responses that appear to enhance MM cell proliferation and survival. This indicates that MM cells can in some cases release TLR activators that trigger responses in the tumor microenvironment that facilitate cancer progression. We are still trying to identify the nature of these activators and have some insight into the their characteristics.
Our main aim is to determine how pattern recognition receptor (PRR) expression and signaling affects cancer progression. PRRs on immune cells recognize molecules associated with infection or injury and mount an inflammatory response. PRRs are promising targets in cancer immunotherapy, but may also be detrimental in tumorigenesis when dysregulated.We are currently studying the cancers multiple myeloma (MM) and colorectal cancer (CRC), since inflammatory responses play important roles in the progression of these cancers. We have concentrated on assessing the role of the signaling PRRs; Toll-Like Receptors (TLR)s and Nod-Like Receptors (NLR)s. We are particularly interested in the role of TLRs 3,7 and 9 in cancer progression, since these are promising targets in cancer immunotherapy due to the potent type I interferon (IFN) immune responses they induce. These TLRs recognize nucleic acids associated with viral infection, or released from injured cells, but can also be triggered by synthetic base-analogs. NLRs sense host molecules released during stress and cell-damage and trigger the inflammatory cytokine IL-1β. Elevated levels of these cytokines are associated with poor prognosis in both CRC and MM.
'We have observed that PRRs may play a role in both CRC and MM. In CRC we have found that metastatic intestinal epithelial cells (IEC)s upregulate certain TLRs, such as TLR3. Altered TLR3 expression and signaling drives the invasiveness of these cells, rather than inducing anti-tumor immunity. We are currently studying the mechanisms of how TLR3 responses drive the invasiveness of cancerous IECs. We have found that chemokines and proteases associated with migration and invasion are upregulated in a TLR3-dependent manner. We also see many of that some of the same molecules are upregulated in tissue biopsies from CRC patients. TLR3 activation in the cancer cells also appears to have important effects on immune cell recruitment to the tumor. Our results indicate that TLR3 has an unexpected role in driving cell migration and invasion and may have role in cancer metastatsis. We are currently performing the last experiments needed to publish these findings.
In MM we have observed that TLR and NLR activators have differential effects on MM cells. Certain TLR7 and NLR activators impair the survival of MM cell lines, and we have confirmed these effects in primary MM cells. We have investigated some mechanisms leading to cell death, but these responses do not seem to be mediated by PRRs. We are still investigating how these activators are sensed, what cell death pathways are activated in MM cells and whether this can be exploited in therapy. In parallel, we have identified that MM cells can release components that activate certain PRRs. These PRRs are expressed on MM cells, as well as PRRs in the tumor micro-environment. We have observed that these components trigger PRR-responses that appear to fuel tumor proliferation and survival. This indicates that MM cells can in some cases produce PRR activators that trigger inflammatory responses in the tumor micro-environment that facilitate cancer progression. We are currently trying to verify our findings and will attempt to identify the nature of these activators.
We aim to determine how pattern recognition receptor (PRR) expression and signaling affects cancer progression. PRRs on immune cells recognize molecules associated with infection or injury and mount an inflammatory response. PRRs are promising targets in cancer immunotherapy, but may also be detrimental in tumorigenesis when dysregulated.We are currently studying the two cancers; multiple myeloma (MM) and colorectal cancer (CRC), since previous results indicated that PRRs play important roles in the progression of these cancers. We have concentrated on assessing the role of the signaling PRRs; Toll-Like Receptors (TLR)s and Nod-Like Receptors (NLR)s. We are particularly interested in the role of TLRs 3,7 and 9 in cancer progression, since these are promising targets in cancer immunotherapy due to the potent type I interferon (IFN) immune responses they induce. These TLRs recognize nucleic acids associated with viral infection, or released from injured cells, but can also be triggered by synthetic base-analogs. NLRs sense host molecules released during stress and cell-damage and trigger the inflammatory cytokine IL-1β. Elevated levels of these cytokines are associated with poor prognosis in both CRC and MM.
We have observed some interesting effects of TLR and NLR activators on CRC and MM cell lines and primary cells. In CRC we have found that non-metastatic and metastatic intestinal epthelial cells (IEC)s respond differently to TLR stimulation. Metastatic IECs upregulate TLR3 and our results indicate that that altered TLR3 expression and signaling in cancerous IECs may in some cases promote the invasiveness of these cells, rather than promote anti-tumor immunity. We are currently dissecting the signaling pathways and immune responses activated by TLR3 which may drive the invasiveness of cancerous IECs by assessing gene expression of 1400 inflammation- and cancer- related genes by Nanostring analysis. We have found that certain chemokines and proteases are upregulated in response to TLR3 stimulation in metastatic IECs and have shown that these components are induced in a TLR3 manner by gene silencing of TLR3. The role of these molecules in mediating the invasive properties of these cells has furthermore been determined by silencing these proteins and performing in vitro invasion and migration assays. We have also performed the same gene expression Nanostring analysis on tissue biopsies from healthy and cancerous tissue in CRC patients and have found similar patterns of expression of several of the chemokines and proteases that were upregulated in cell lines in response to TLR3 activation. Our results indicate that TLR3 may have an unexpected role in the progression of CRC and that blocking TLR3 signaling may prove beneficial in some cases.
In MM, we have previously assessed the effect of TLR and NLR activators on MM cell survival and found that certain TLR7 and NLR activators impair the survival of MM cell lines and primary MM cells. This was a surprising finding since these activators typically induce signaling molecules that promote MM survival. We have verified that TLR7 and NLR activators induce apoptosis in MM cell lines and primary cells. We have assessed cleavage of several caspases involved in cell death and have identified some cell death mechanisms, but it is still unclear whether these responses are mediated by TLR7 and NLRs or by other receptors. We are in the process of investigating mechanisms of how these activators induce cell death in MM cells and have results indicating that some unexpected pathways are activated by these activators. We are currently verifying these findings are and investigating whether this can be exploited in therapy.
This project aims to provide new insight into how pattern recognition receptor (PRR) expression and signaling affects the progression of the cancers mutliple myeloma and colorectal cancer. PRRs expressed on immune cells recognize molecules associated with infection and injury, but may also play important roles during the progression of cancer.Pattern recognition receptors (PRR)s are highly expressed on immune cells and serve to recognize molecules associated with infection, stress or injury. Upon recognition of such factors, PRRs mount an inflammatory response which protects the host during the early phases of infection. PRRs can promote anti-tumor immune responses and are promising targets in cancer immunotherapy. PRRs may, however, play detrimental roles in tumorigenesis by mediating chronic inflammation when dysregulated. We are currently studying the two cancers multiple myeloma (MM) and colorectal cancer (CRC), since previous results indicated that PRRs play important roles in the progression of these cancers. We have focused on assessing the role of the signaling PRRs; Toll-Like Receptors (TLR)s and Nod-Like Receptors (NLR)s. We are particularly interested in the role of TLRs 3,7 and 9 in cancer progression, since these are promising targets in cancer immunotherapy due to the potent type I IFN immune responses they induce. These TLRs recognize nucleic acids associated with viral infection, or released from injured cells, but can also be triggered by synthetic base-analogs. NLRs sense host molecules released during stress and cell-damage and trigger the inflammatory cytokine IL-1β. Elevated levels of these cytokines are associated with poor prognosis in both CRC and MM. We have assessed the effect of TLR and NLR activators on CRC and MM cell lines and primary cells to determine the outcome of PRR stimulation on these cells.
We have found that helathy, non-metastatic and metastatic intestinal epithelial cells (IEC)s respond differently to TLR stimulation. Metastatic IECs upregulate TLR3 and respond potently to TLR3 activators, in contrast to healthy and non-metastatic IECs. We have further found that activation of TLR3 induces an altered cytokine response characterized by potent chemokine production, but no type I IFN induction. TLR3 activation further promotes the invasive capacity of these cells. Our results indicate that altered TLR3 expression in cancerous IECs may in some cases promotes inflammation and the invasiveness of these cells, rather than triggering anti-tumor immunity. We are currently investigating if these findings can be verified in biopsies from CRC patients. We are also assessing the expression of TLRs, NLRs and inflammatory genes in tissue biopsies from CRC patients at different stages to determine how expression correlates with stage and markers of prognosis.
In MM, we have previously found that certain TLR7 and NLR activators impair the growth and survival of MM cells. This is unexpected since TLR7 activators have previously been shown to promote MM survival. NLR activation also induces IL1β production, which is known to enhance MM survival. Primary MM cells from patients displayed sensitivity to the same activators. Although blood cells from healthy individuals generally tolerated these activators relatively well, we observed a partial reduction in cell survival which we have pin-pointed to the B cell population. This suggests that B cells may be particularly sensitive to these activators. We are currently investigating the mechanisms underlying how these activators induce cell death in MM cells and B cells. We are also assessing the signaling pathways which are activated in response to these activators to determine if this can be exploited in therapy.
We aim to provide new insight into how PRR expression and signaling affects the progression of the cancers colorectal cancer (CRC) and multiple myeloma (MM). We found unexpected effects of PRR expression and signaling in MM and CRC. Our findings require further study, but appear to have implications for diagnosis and treatment of these cancers.This project aims to provide new insight into how pattern recognition receptor (PRR) expression and signaling affects the progression of the cancer. PRRs expressed on immune cells recognize molecules associated with infection, stress or injury. Upon recognition of such factors, PRRs mount an inflammatory response which protects the host during the early phases of infection.PRRs can promote anti-tumor immune responses and are promising targets in cancer immunotherapy. PRRs may, however, play detrimental roles in tumorigenesis by mediating chronic inflammation when dysregulated.
We are studying the two cancers; multiple myeloma (MM) and colorectal cancer (CRC), since previous results indicated that PRRs play important roles in the progression of these cancers. We have concentrated on assessing the role of the signaling PRRs; Toll-Like Receptors (TLR)s and Nod-Like Receptors (NLR)s. We are particularly interested in the role of TLRs 3,7 and 9 in cancer progression, since these are promising targets in cancer immunotherapy due to the potent type I IFN immune responses they induce. These TLRs recognize nucleic acids associated with viral infection, or released from injured cells, but can also be triggered by synthetic base-analogs. NLRs sense host molecules released during stress and cell-damage and trigger the inflammatory cytokine IL-1ß. Elevated levels of these cytokines are associated with poor prognosis in both CRC and MM.
We have assessed the effect of TLR and NLR activators on CRC and MM cell lines and primary cells to determine the outcome of PRR stimulation on these cells. We have found that non-metastatic and metastatic intestinal epithelial cells (IEC)s respond differently to TLR stimulation. Metastatic IECs upregulate TLR3 and respond potently to TLR3 activators, in contrast to healthy and non-metastatic IECs. We have further found that activation of TLR3 induces an altered cytokine response characterized by potent chemokine production, but no type I IFN induction. TLR3 activation further promotes the invasive capacity of these cells. Our results indicate that altered TLR3 expression in cancerous IECs may in some cases promote the invasiveness of these cells, rather than promote anti-tumor immunity. We are currently revising a manuscript describing these findings. We further aim to verify these findings in patient samples.
We have also assessed the effect of TLR and NLR activators on MM cell survival. Although stimulation with several PRR activators enhances survival of these cells, we have found that certain TLR7 and NLR activators impair the survival of these cells. This is surprising since TLR7 activators have previously been shown to promote MM survival. NLR activation also induces IL1ß production, which is known to enhance MM survival. We have also found that primary MM cells from patients display sensitivity to the same activators, while blood cells from healthy individuals tolerate these activators relatively well. Our data indicate that these activators induce apoptosis in MM cells rapidly. We are currently verifying these data, as well as investigating alternative mechanisms of cell death which are known to be induced by NLRs. We are currently assessing TLR7 and NLR expression in MM cells. We are also determining the signaling pathways which are activated in response to these ligands to determine why these cells are particularly sensitive to TLR7 and NLR activators, and whether this can be exploited in therapy.
Vitenskapelige artikler
Bugge M, Bergstrom B, Eide OK, Solli H, Kjønstad IF, Stenvik J, Espevik T, Nilsen NJ
Surface Toll-like receptor 3 expression in metastatic intestinal epithelial cells induces inflammatory cytokine production and promotes invasiveness.
J Biol Chem 2017 09 15;292(37):15408-15425. Epub 2017 jul 17
PMID: 28717003
Doktorgrader
Marit Bugge
Toll-Like Receptor 3 in Intestinal Epithelial Cells
- Disputert:
- april 2016
- Hovedveileder:
- Nadra Jesmine Nilsen
Deltagere
- Eicke Latz Prosjektdeltaker
- Katherine A. Fitzgerald Prosjektdeltaker
- Egil Lien Prosjektdeltaker
- Marit Bugge Postdoktorstipendiat
- Eva Hofsli Prosjektdeltaker
- Anders Waage Prosjektdeltaker
- Therese Standal Prosjektdeltaker
- Anders Sundan Prosjektdeltaker
- Terje Espevik Prosjektdeltaker
- Nadra Jesmine Nilsen Prosjektleder
eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT
Alle henvendelser rettes til Helse Midt-Norge RHF - Samarbeidsorganet og FFU