-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
- Cosmetic Ingredient
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Editor | The unknown mechanism of strong immunosuppression in the tumor microenvironment has been a research hotspot in recent years
.
Answering key questions in these mechanisms will further advance the effectiveness of tumor immunotherapy in more people
.
Metabolic disorders or metabolic changes are a major feature of tumor cells
.
A large number of research evidences in recent years have shown that the tumor microenvironment (TME) has significantly different metabolic characteristics from normal tissue environment or blood [1,2], and how metabolic pathways regulate tumor immune response is an important factor.
Problem
.
One of the characteristics of the tumor microenvironment is the disorder and imbalance of lipid metabolism, which is mainly manifested by lipid enrichment
.
Increased lipid absorption (including fatty acids, cholesterol) and intracellular neutral lipid enrichment not only inhibit the anti-tumor immune response, but enhance the tumor-promoting immune response
.
The tumor-infiltrating immune cells affected by this include antigen-presenting dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, regulatory CD4 T cells (Treg), and Cytotoxic CD8 T cells
.
On June 7, 2021, the Susan Kaech team of the Salk Institute and the Cui Guoliang team of the German Cancer Research Center (Dr.
Xu Shihao as the first author) published a titled Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid in Immunity.
peroxidation and dysfunction in CD8+ T cells in tumors
.
In the article, the author mainly discussed how CD8 T cells adapt to the tumor microenvironment at the level of lipid metabolism, and how their metabolic changes affect their tumor-killing immune response
.
The authors found that in the tumor microenvironment, the content of various lipids increased, especially oxidized phospholipids; the intracellular lipid content of tumor-infiltrating CD8 T cells (CD8 TILs) increased
.
At the same time, dysfunctional tumor-infiltrating CD8 T cells increase the expression of lipid membrane receptor CD36 molecules
.
The author discovered for the first time that CD36 molecules on the surface of tumor-infiltrating CD8 T cells absorb oxidized low-density lipoprotein (OxLDL), activate lipid peroxidation, and thereby inhibit the effector function of CD8 cells
.
First, in order to understand which lipids and their concentration changes are contained in the tumor microenvironment, the author used a mouse subcutaneous tumor model to separate tumor interstitial fluid (TIF), and together with the separated serum, the lipid mass spectrometry was performed
.
The results showed that the content of free fatty acids, acyl carnitine, and cholesterol ester in the tumor tissue fluid was significantly increased
.
In order to further understand the response of tumor-infiltrating CD8 T cells to the high-fat tumor microenvironment, combined with flow cytometry, the authors tested the lipid uptake and intracellular lipid content of tumor-infiltrating CD8 T cells
.
The results showed that tumor-infiltrating CD8 T cells enhanced the uptake of different lipids, including fatty acids and cholesterol, and increased intracellular lipid content
.
Unsaturated fatty acids are easily oxidized by free radicals, and the oxidized lipids are unstable, which can mediate oxidative stress-related and iron-dependent programmed cell death, also known as ferroptosis
.
Through immunohistochemical staining, the authors found that tumors contain higher levels of oxidized phospholipids than normal tissues
.
At the same time, tumor-infiltrating CD8 T cells increased the absorption of OxLDL and lipid peroxidation
.
These results indicate that tumor-infiltrating CD8 T cells do have adaptations or changes in lipid metabolism in the high-fat tumor microenvironment
.
The transmembrane transport of lipids usually depends on the membrane receptors or transporters of various lipids
.
By combining genomic expression profiling and flow cytometry, the authors found that tumor-infiltrating CD8 T cells up-regulated the expression of the lipid receptor CD36, especially in terminally exhausted CD8 TILs
.
Human-derived tumor-infiltrating CD8 T cells have similar characteristics
.
In order to understand whether CD36 is involved in regulating the anti-tumor function of CD8 T cells, the authors used a CD36 knockout transgenic mouse model and found that CD36 knockout (Cd36-/-) CD8 T cells are better than wild-type (Cd36+/+) CD8 T cells.
Cells have stronger anti-tumor function and activity
.
These experimental results show that the high expression level of CD36 is not only related to the dysfunction of tumor-infiltrating CD8 T cells, but also directly involved in regulating the anti-tumor function of CD8 T cells
.
As a lipid receptor, CD36 participates in the binding and absorption of various lipids in different cells
.
In order to understand whether CD36 binds certain lipids in CD8 T cells, the authors compared the absorption of various lipids by Cd36-/- and Cd36+/+ cells
.
The results showed that compared with Cd36+/+ cells, Cd36-/- cells had no significant difference in the absorption of long-chain or medium-chain fatty acids or cholesterol, or the content of intracellular neutral lipids, or the mitochondrial oxidation of fatty acids.
.
However, in the absorption of OxLDL, Cd36-/- cells have a significant decrease
.
Through imaging flow cytometry, the authors found that OxLDL co-localizes with CD36 in the cell membrane
.
These experimental results indicate that the CD36 molecules on tumor-infiltrating CD8 T cells are involved in the absorption of OxLDL
.
In order to further clarify how CD36 and OxLDL regulate CD8 T cells, the authors found that OxLDL inhibits the effector function of CD8 T cells through CD36
.
The immunosuppressive function of OxLDL on CD8 T cells is through the activation of lipid peroxidation and downstream p38 kinase
.
In order to test whether lipid peroxidation can be regulated to change the anti-tumor function of CD8 T cells, the authors overexpressed glutathione-peroxidized lipid degrading enzyme (GPX4) in CD8 T cells and adopted it into tumor-bearing mice
.
The results showed that, compared with the control group, GPX4 overexpressed CD8 T cells showed stronger tumor suppressor activity, which was accompanied by higher effector functions
.
Figure 1 Oxidized lipids are a significant feature of inflammation, including atherosclerosis, but its role in the tumor microenvironment is not clear
.
This paper shows a new immunosuppressive mode in the tumor microenvironment: through high expression of the lipid receptor CD36, tumor-infiltrating CD8 T cells absorb oxidized low-density lipoproteins, increase lipid peroxidation, and enhance p38 kinase activity, thereby Loss of its anti-tumor effector function (Figure 1)
.
Recently, p38 kinase has also been found to be involved in negatively regulating the anti-tumor function of tumor-infiltrating CD8 T cells [3]
.
Too high lipid peroxide can trigger iron death of cells
.
Another recent paper found a very similar result: CD36 inhibits the anti-tumor function of CD8 T cells by regulating lipid peroxidation and cell iron death (see BioArt report: Cell Metab | Yi Qing team reveals that the lipid metabolism molecule CD36 regulates tumors The new mechanism of internal CD8+ T cell function) [4]
.
The transport of most fatty acids or other lipids depends on lipoproteins or albumin, and apoptotic cells in tumors produce large amounts of highly active oxidized lipids
.
The results of the study further clarify that oxidized lipids or oxidized low-density lipoproteins, through the lipid receptor CD36, which is highly expressed by CD8 T cells, activate p38 to affect the effector function of CD8 T cells
.
Iron death based on lipid peroxidation has attracted widespread attention in oncology in recent years, and glutathione-peroxidase lipolytic enzyme GPX4 is a key target for inducing iron death
.
The paper shows that GPX4 also plays an important role in the anti-tumor activity of CD8 T cells
.
At this point, the researchers believe that treatment options based on inhibiting GPX4 to induce tumor iron death need to avoid side effects on CD8 T cells
.
In addition to the role of CD36 in CD8 T cells, other studies in recent years have shown that CD36 can regulate the lipid metabolism, survival and function of Treg cells in tumors [5]; it participates in regulating the metabolism and survival of cancer stem cells [6, 7], indicating CD36 can be used as an important multi-directional tumor treatment target
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
05.
003 Platemaker: 11 References 1.
Buck, MD, Sowell, RT, Kaech, SM, and Pearce, EL (2017).
Metabolic Instruction of Immunity.
Cell 169, 570-586.
2.
Sullivan, MR, Danai, LV, Lewis, CA, Chan, SH, Gui, DY, Kunchok, T.
, Dennstedt, EA, Vander Heiden, MG, and Muir, A.
(2019).
Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability.
eLife 8, e44235.
3.
Gurusamy, D.
, Henning, AN, Yamamoto, TN, Yu, Z.
, Zacharakis, N.
, Krishna, S.
, Kishton, RJ, Vodnala, SK, Eidizadeh, A.
, Jia, L.
, et al.
(2020).
Multiphenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies.
Cancer Cell 37, 818–833 .
e9.
4.
Ma, X.
, Xiao, L.
, Liu, L.
, Ye, L.
, Su, P.
, Bi, E.
, Wang, Q.
, Yang, M.
, Qian, J.
, and Yi, Q.
(2021).
CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability.
Cell Metab.
33, 1001–1012.
e5.
5.
Wang, H.
, Franco, F.
, Tsui, YC, Xie, X.
, Trefny , MP, Zappasodi, R.
, Mohmood, SR, Ferna´ ndez-Garcı´a, J.
, Tsai, CH, Schulze, I.
, et al.
(2020).
CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.
Nat.
Immunol.
21, 298–308.
6.
Ye, H.
, Adane, B.
, Khan, N.
, Sullivan, T.
, Minhajuddin, M.
, Gasparetto, M.
, Stevens, B.
, Pei , S.
, Balys, M.
, Ashton, JM, et al.
(2016).
Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche.
Cell Stem Cell 19, 23–37.
7.
Pascual, G.
, Avgustinova, A.
, Mejetta, S.
, Martı´n, M.
, Castellanos, A.
, Attolini, CSO, Berenguer, A.
, Prats, N.
, Toll, A.
, Hueto, JA, et al.
(2017).
Targeting metastasis-initiating cells through the fatty acid receptor CD36.
Nature 541, 41–45.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Offenders must be investigated
.
.
Answering key questions in these mechanisms will further advance the effectiveness of tumor immunotherapy in more people
.
Metabolic disorders or metabolic changes are a major feature of tumor cells
.
A large number of research evidences in recent years have shown that the tumor microenvironment (TME) has significantly different metabolic characteristics from normal tissue environment or blood [1,2], and how metabolic pathways regulate tumor immune response is an important factor.
Problem
.
One of the characteristics of the tumor microenvironment is the disorder and imbalance of lipid metabolism, which is mainly manifested by lipid enrichment
.
Increased lipid absorption (including fatty acids, cholesterol) and intracellular neutral lipid enrichment not only inhibit the anti-tumor immune response, but enhance the tumor-promoting immune response
.
The tumor-infiltrating immune cells affected by this include antigen-presenting dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, regulatory CD4 T cells (Treg), and Cytotoxic CD8 T cells
.
On June 7, 2021, the Susan Kaech team of the Salk Institute and the Cui Guoliang team of the German Cancer Research Center (Dr.
Xu Shihao as the first author) published a titled Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid in Immunity.
peroxidation and dysfunction in CD8+ T cells in tumors
.
In the article, the author mainly discussed how CD8 T cells adapt to the tumor microenvironment at the level of lipid metabolism, and how their metabolic changes affect their tumor-killing immune response
.
The authors found that in the tumor microenvironment, the content of various lipids increased, especially oxidized phospholipids; the intracellular lipid content of tumor-infiltrating CD8 T cells (CD8 TILs) increased
.
At the same time, dysfunctional tumor-infiltrating CD8 T cells increase the expression of lipid membrane receptor CD36 molecules
.
The author discovered for the first time that CD36 molecules on the surface of tumor-infiltrating CD8 T cells absorb oxidized low-density lipoprotein (OxLDL), activate lipid peroxidation, and thereby inhibit the effector function of CD8 cells
.
First, in order to understand which lipids and their concentration changes are contained in the tumor microenvironment, the author used a mouse subcutaneous tumor model to separate tumor interstitial fluid (TIF), and together with the separated serum, the lipid mass spectrometry was performed
.
The results showed that the content of free fatty acids, acyl carnitine, and cholesterol ester in the tumor tissue fluid was significantly increased
.
In order to further understand the response of tumor-infiltrating CD8 T cells to the high-fat tumor microenvironment, combined with flow cytometry, the authors tested the lipid uptake and intracellular lipid content of tumor-infiltrating CD8 T cells
.
The results showed that tumor-infiltrating CD8 T cells enhanced the uptake of different lipids, including fatty acids and cholesterol, and increased intracellular lipid content
.
Unsaturated fatty acids are easily oxidized by free radicals, and the oxidized lipids are unstable, which can mediate oxidative stress-related and iron-dependent programmed cell death, also known as ferroptosis
.
Through immunohistochemical staining, the authors found that tumors contain higher levels of oxidized phospholipids than normal tissues
.
At the same time, tumor-infiltrating CD8 T cells increased the absorption of OxLDL and lipid peroxidation
.
These results indicate that tumor-infiltrating CD8 T cells do have adaptations or changes in lipid metabolism in the high-fat tumor microenvironment
.
The transmembrane transport of lipids usually depends on the membrane receptors or transporters of various lipids
.
By combining genomic expression profiling and flow cytometry, the authors found that tumor-infiltrating CD8 T cells up-regulated the expression of the lipid receptor CD36, especially in terminally exhausted CD8 TILs
.
Human-derived tumor-infiltrating CD8 T cells have similar characteristics
.
In order to understand whether CD36 is involved in regulating the anti-tumor function of CD8 T cells, the authors used a CD36 knockout transgenic mouse model and found that CD36 knockout (Cd36-/-) CD8 T cells are better than wild-type (Cd36+/+) CD8 T cells.
Cells have stronger anti-tumor function and activity
.
These experimental results show that the high expression level of CD36 is not only related to the dysfunction of tumor-infiltrating CD8 T cells, but also directly involved in regulating the anti-tumor function of CD8 T cells
.
As a lipid receptor, CD36 participates in the binding and absorption of various lipids in different cells
.
In order to understand whether CD36 binds certain lipids in CD8 T cells, the authors compared the absorption of various lipids by Cd36-/- and Cd36+/+ cells
.
The results showed that compared with Cd36+/+ cells, Cd36-/- cells had no significant difference in the absorption of long-chain or medium-chain fatty acids or cholesterol, or the content of intracellular neutral lipids, or the mitochondrial oxidation of fatty acids.
.
However, in the absorption of OxLDL, Cd36-/- cells have a significant decrease
.
Through imaging flow cytometry, the authors found that OxLDL co-localizes with CD36 in the cell membrane
.
These experimental results indicate that the CD36 molecules on tumor-infiltrating CD8 T cells are involved in the absorption of OxLDL
.
In order to further clarify how CD36 and OxLDL regulate CD8 T cells, the authors found that OxLDL inhibits the effector function of CD8 T cells through CD36
.
The immunosuppressive function of OxLDL on CD8 T cells is through the activation of lipid peroxidation and downstream p38 kinase
.
In order to test whether lipid peroxidation can be regulated to change the anti-tumor function of CD8 T cells, the authors overexpressed glutathione-peroxidized lipid degrading enzyme (GPX4) in CD8 T cells and adopted it into tumor-bearing mice
.
The results showed that, compared with the control group, GPX4 overexpressed CD8 T cells showed stronger tumor suppressor activity, which was accompanied by higher effector functions
.
Figure 1 Oxidized lipids are a significant feature of inflammation, including atherosclerosis, but its role in the tumor microenvironment is not clear
.
This paper shows a new immunosuppressive mode in the tumor microenvironment: through high expression of the lipid receptor CD36, tumor-infiltrating CD8 T cells absorb oxidized low-density lipoproteins, increase lipid peroxidation, and enhance p38 kinase activity, thereby Loss of its anti-tumor effector function (Figure 1)
.
Recently, p38 kinase has also been found to be involved in negatively regulating the anti-tumor function of tumor-infiltrating CD8 T cells [3]
.
Too high lipid peroxide can trigger iron death of cells
.
Another recent paper found a very similar result: CD36 inhibits the anti-tumor function of CD8 T cells by regulating lipid peroxidation and cell iron death (see BioArt report: Cell Metab | Yi Qing team reveals that the lipid metabolism molecule CD36 regulates tumors The new mechanism of internal CD8+ T cell function) [4]
.
The transport of most fatty acids or other lipids depends on lipoproteins or albumin, and apoptotic cells in tumors produce large amounts of highly active oxidized lipids
.
The results of the study further clarify that oxidized lipids or oxidized low-density lipoproteins, through the lipid receptor CD36, which is highly expressed by CD8 T cells, activate p38 to affect the effector function of CD8 T cells
.
Iron death based on lipid peroxidation has attracted widespread attention in oncology in recent years, and glutathione-peroxidase lipolytic enzyme GPX4 is a key target for inducing iron death
.
The paper shows that GPX4 also plays an important role in the anti-tumor activity of CD8 T cells
.
At this point, the researchers believe that treatment options based on inhibiting GPX4 to induce tumor iron death need to avoid side effects on CD8 T cells
.
In addition to the role of CD36 in CD8 T cells, other studies in recent years have shown that CD36 can regulate the lipid metabolism, survival and function of Treg cells in tumors [5]; it participates in regulating the metabolism and survival of cancer stem cells [6, 7], indicating CD36 can be used as an important multi-directional tumor treatment target
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
05.
003 Platemaker: 11 References 1.
Buck, MD, Sowell, RT, Kaech, SM, and Pearce, EL (2017).
Metabolic Instruction of Immunity.
Cell 169, 570-586.
2.
Sullivan, MR, Danai, LV, Lewis, CA, Chan, SH, Gui, DY, Kunchok, T.
, Dennstedt, EA, Vander Heiden, MG, and Muir, A.
(2019).
Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability.
eLife 8, e44235.
3.
Gurusamy, D.
, Henning, AN, Yamamoto, TN, Yu, Z.
, Zacharakis, N.
, Krishna, S.
, Kishton, RJ, Vodnala, SK, Eidizadeh, A.
, Jia, L.
, et al.
(2020).
Multiphenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies.
Cancer Cell 37, 818–833 .
e9.
4.
Ma, X.
, Xiao, L.
, Liu, L.
, Ye, L.
, Su, P.
, Bi, E.
, Wang, Q.
, Yang, M.
, Qian, J.
, and Yi, Q.
(2021).
CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability.
Cell Metab.
33, 1001–1012.
e5.
5.
Wang, H.
, Franco, F.
, Tsui, YC, Xie, X.
, Trefny , MP, Zappasodi, R.
, Mohmood, SR, Ferna´ ndez-Garcı´a, J.
, Tsai, CH, Schulze, I.
, et al.
(2020).
CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.
Nat.
Immunol.
21, 298–308.
6.
Ye, H.
, Adane, B.
, Khan, N.
, Sullivan, T.
, Minhajuddin, M.
, Gasparetto, M.
, Stevens, B.
, Pei , S.
, Balys, M.
, Ashton, JM, et al.
(2016).
Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche.
Cell Stem Cell 19, 23–37.
7.
Pascual, G.
, Avgustinova, A.
, Mejetta, S.
, Martı´n, M.
, Castellanos, A.
, Attolini, CSO, Berenguer, A.
, Prats, N.
, Toll, A.
, Hueto, JA, et al.
(2017).
Targeting metastasis-initiating cells through the fatty acid receptor CD36.
Nature 541, 41–45.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Offenders must be investigated
.
