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As a revolutionary treatment method, Immune Checkpoint Inhibitor Therapy (ICBT) has achieved unprecedented success in cancer treatment.
It has a wide range of treatments, and it can treat a variety of cancers such as lung cancer, kidney cancer, colorectal cancer and melanoma.
Once the patient responds to the treatment, the response time is long [1], and it can even play an anti-tumor effect in the case of metastasis [2].
Unfortunately, most patients do not respond to ICBT [3].
For example, the effective rate of ICBT in patients with highly microsatellite unstable colorectal cancer (MSI-H-CRC) is between 30% and 60%, but it accounts for a larger proportion of microsatellite stable colorectal cancer (MSS).
-CRC) The patient hardly responds to ICBT.
Recently, the team of Professor Subbaya Subramanian of the University of Minnesota School of Medicine published an important research result in the journal Gastroenterology, and found the internal mechanism that affects the effect of immunotherapy for colorectal cancer.
They found that extracellular vesicles (TEVs) containing miR-424 secreted by intestinal cancer cells can be taken up by infiltrating immune cells in the tumor microenvironment, resulting in a decrease in the expression of CD28 and CD80 of T cells and dendritic cells (DCs).
Destroy the T cell costimulatory signal transmission, resulting in the inability of T cells to be fully activated to produce an anti-tumor response, causing patients to resist immunotherapy.
Researchers also found that as long as the extravesicles derived from intestinal cancer cells do not contain miR-424, and then combined with ICBT to treat metastatic CRC, the therapeutic effect of ICBT will be improved [4].
The study revealed that tumor-derived vesicles can act as immunosuppressive factors to destroy the anti-tumor immune response of the immune system in the body.
In addition, the use of modified tumor extracellular vesicles has immunogenic properties, which can reduce the drug resistance of immunotherapy.
We all know that only activated T cells can play an anti-tumor effect.
To achieve complete activation, two kinds of signal stimulation are needed.
First, antigen-presenting cells (APC) present processed antigens to TCR receptors on the surface of T cells through MHC on their surface, and activate CD3 and its co-receptor CD4 or CD8.
Start the transcription of cell activation-related molecular genes to complete the initial activation; then CD28 on the surface of T cells combines with CD80/CD86 on the surface of APC cells as a costimulatory signal to induce T cells to express a series of cytokines and cytokine receptors.
It is not difficult to see that the CD28-CD80/86 costimulatory signal is very important for ICBT response.
So is the low efficiency of ICBT response or non-response caused by the incomplete activation of T cells in the tumor microenvironment? Sure enough, based on the data of human colon cancer tissue samples and the TCGA-CRC database, the researchers found that the costimulatory molecules CD28, CD80, and CD86 were down-regulated in human CRC infiltrating T cells and dendritic cells (DCs).
They also confirmed through experiments that the CD28-CD80/86 costimulatory signaling pathway is a necessary condition for immune checkpoint inhibitor therapy to respond.
In MSS-CRC patients, T cells and DCs cells express low CD28, CD80 and CD86.
ICBT has no effect in CD28, CD80/CD86 KO mice.
The next question they asked is: What is the reason for the down-regulation of CD28, CD80 and CD86? Is it caused by post-transcriptional regulation? To find out why, the researchers screened out microRNAs (miRNAs) that can bind to CD28 and CD80/CD86 mRNA.
MicroRNA is a type of non-coding RNA with a length of about 21 nucleotides that regulates the expression of genes after transcription.
It binds to the 3'UTR of the target mRNA in a way of incomplete base pairing, and prevents it by inhibiting protein translation or promoting mRNA degradation.
Protein synthesis [5].
The researchers quickly found a microRNA called miR-424.
They found that miR-424 can simultaneously target the 3'UTR of CD28 and CD80 mRNA, and can inhibit the expression of CD28 and CD80 in T cells and dendritic cells.
What puzzles researchers is: clinical CRC samples and TCGA data analysis show that miR-424 is mainly expressed in CRC cells, and the expression level in T cells and DCs is very low.
How does miR-424 in cancer cells affect T cells and DCs? The strange phenomenon that MiR-424 reduced the expression of CD28 and CD80 on the surface of T cells and DCs led researchers to speculate that the lower expression of CD28 and CD80 in infiltrating T cells and DCs was caused by miR-424 secreted by CRC cells.
In order to confirm the above conjecture, the researchers first found that the extracellular vesicles (TEVs) secreted by CRC cancer cells are indeed rich in miR-424, and that tumor-infiltrating T cells and DCs cells can ingest TEVs containing miR-424 secreted by CRC.
And cause its CD28 and CD80 expression to decrease.
As we all know, extracellular vesicles (EVs) are lipid bilayer spheres released by cells that are encapsulated with DNA, RNA, lipids, cytoplasm and cell membrane proteins.
A large number of studies have shown that EVs are important mediators of cell-to-cell communication and are involved in a variety of physiological and pathological processes such as immune response, growth and development, metabolism and heart disease, neurodegeneration, and tumors [6].
Since miRNA-424 is the crux of the problem, can inhibiting miRNA-424 in CRC-derived EVs inhibit tumor growth? The researchers subcutaneously transplanted miRNA-424 knock-out CRC cells into mice.
Compared with the control group, tumors injected with miR-424 EVs grew faster, and the expression of CD28 and CD80 in the tumor infiltrating immune cells decreased.
The researchers also used Cd28-/-, Cd80/86-/- and other immunodeficient mice to verify that the tumor-promoting effect of miR-424 depends on the CD28-CD80/86 costimulatory signal.
Subsequent studies also found that inhibiting the expression of miR-424 in CRC cells changed the tumor microenvironment: In addition to the increased expression of CD28 and CD80 in infiltrating T cells and DCs cells, the amount of immune cell infiltration and IL-2 production were also enhanced.
As a result, the therapeutic effect of anti-PD-1/CTLA-4 drugs on advanced tumors is naturally improved.
Since TEVs containing miR-424 have immunosuppressive effects, after miR-424 is removed from TEVs, can TEVs produce immunogenic anti-tumor responses that activate T cells? The researchers then injected EVs derived from CRC cells that did not contain miR-424 into mice and found that it activated the proliferation of tumor antigen-specific CD8+ T cells in peripheral lymphoid organs, indicating that the modified EVs are immunogenic.
In the cecal orthotopic CRC late-stage mouse model, the modified EVs combined with anti-PD-1/CTLA-4 drugs has a 50% higher survival rate than anti-PD-1/CTLA-4 drugs alone, and reduces metastases.
It shows that the modified EVs have certain clinical therapeutic significance.
All in all, the study shows that tumor-derived extracellular vesicles contain immunosuppressive molecules that help tumor cells to escape immune.
In ICBT treatment, keeping the costimulatory signaling pathway in an active state is as important as inhibiting the co-inhibitory signaling pathway.
Removal of immunosuppressive factors in tumor-derived EVs can eliminate their immunosuppressive effects, and can be used as an adjuvant for immunotherapy to improve treatment efficiency and establish a treatment strategy based on EVs.
References[1] Wei SC, Duffy CR, Allison JP.
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy.
Cancer Discov.
2018;8(9):1069-1086.
doi:10.
1158/2159-8290.
CD-18-0367[ 2] Hodi FS, O'Day SJ, McDermott DF, et al.
Improved survival with ipilimumab in patients with metastatic melanoma [published correction appears in N Engl J Med.
2010 Sep 23;363(13):1290].
N Engl J Med.
2010;363(8):711-723.
doi:10.
1056/NEJMoa1003466[3] Pitt JM, Vétizou M, Daillère R, et al.
Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors Immunity.
2016;44(6):1255-1269.
doi:10.
1016/j.
immuni.
2016.
06.
001[4] Zhao X, Yuan C, Wangmo D, Subramanian S.
Tumor secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumor specific T-cell responses [published online ahead of print, 2021 Apr 22.
Gastroenterology.
2021;S0016-5085(21)00660-0.
doi:10.
1053/j.
gastro.
2021.
04.
036[5] Krol J, Loedige I, Filipowicz W.
The widespread regulation of microRNA biogenesis, function and decay.
Nat Rev Genet.
2010;11(9):597-610.
doi:10.
1038/nrg2843[6] Kalluri R, LeBleu VS.
The biology, function, and biomedical applications of exosomes.
Science.
2020;367(6478):eaau6977.
doi :10.
1126/science.
aau6977 Responsible EditorBioTalker
It has a wide range of treatments, and it can treat a variety of cancers such as lung cancer, kidney cancer, colorectal cancer and melanoma.
Once the patient responds to the treatment, the response time is long [1], and it can even play an anti-tumor effect in the case of metastasis [2].
Unfortunately, most patients do not respond to ICBT [3].
For example, the effective rate of ICBT in patients with highly microsatellite unstable colorectal cancer (MSI-H-CRC) is between 30% and 60%, but it accounts for a larger proportion of microsatellite stable colorectal cancer (MSS).
-CRC) The patient hardly responds to ICBT.
Recently, the team of Professor Subbaya Subramanian of the University of Minnesota School of Medicine published an important research result in the journal Gastroenterology, and found the internal mechanism that affects the effect of immunotherapy for colorectal cancer.
They found that extracellular vesicles (TEVs) containing miR-424 secreted by intestinal cancer cells can be taken up by infiltrating immune cells in the tumor microenvironment, resulting in a decrease in the expression of CD28 and CD80 of T cells and dendritic cells (DCs).
Destroy the T cell costimulatory signal transmission, resulting in the inability of T cells to be fully activated to produce an anti-tumor response, causing patients to resist immunotherapy.
Researchers also found that as long as the extravesicles derived from intestinal cancer cells do not contain miR-424, and then combined with ICBT to treat metastatic CRC, the therapeutic effect of ICBT will be improved [4].
The study revealed that tumor-derived vesicles can act as immunosuppressive factors to destroy the anti-tumor immune response of the immune system in the body.
In addition, the use of modified tumor extracellular vesicles has immunogenic properties, which can reduce the drug resistance of immunotherapy.
We all know that only activated T cells can play an anti-tumor effect.
To achieve complete activation, two kinds of signal stimulation are needed.
First, antigen-presenting cells (APC) present processed antigens to TCR receptors on the surface of T cells through MHC on their surface, and activate CD3 and its co-receptor CD4 or CD8.
Start the transcription of cell activation-related molecular genes to complete the initial activation; then CD28 on the surface of T cells combines with CD80/CD86 on the surface of APC cells as a costimulatory signal to induce T cells to express a series of cytokines and cytokine receptors.
It is not difficult to see that the CD28-CD80/86 costimulatory signal is very important for ICBT response.
So is the low efficiency of ICBT response or non-response caused by the incomplete activation of T cells in the tumor microenvironment? Sure enough, based on the data of human colon cancer tissue samples and the TCGA-CRC database, the researchers found that the costimulatory molecules CD28, CD80, and CD86 were down-regulated in human CRC infiltrating T cells and dendritic cells (DCs).
They also confirmed through experiments that the CD28-CD80/86 costimulatory signaling pathway is a necessary condition for immune checkpoint inhibitor therapy to respond.
In MSS-CRC patients, T cells and DCs cells express low CD28, CD80 and CD86.
ICBT has no effect in CD28, CD80/CD86 KO mice.
The next question they asked is: What is the reason for the down-regulation of CD28, CD80 and CD86? Is it caused by post-transcriptional regulation? To find out why, the researchers screened out microRNAs (miRNAs) that can bind to CD28 and CD80/CD86 mRNA.
MicroRNA is a type of non-coding RNA with a length of about 21 nucleotides that regulates the expression of genes after transcription.
It binds to the 3'UTR of the target mRNA in a way of incomplete base pairing, and prevents it by inhibiting protein translation or promoting mRNA degradation.
Protein synthesis [5].
The researchers quickly found a microRNA called miR-424.
They found that miR-424 can simultaneously target the 3'UTR of CD28 and CD80 mRNA, and can inhibit the expression of CD28 and CD80 in T cells and dendritic cells.
What puzzles researchers is: clinical CRC samples and TCGA data analysis show that miR-424 is mainly expressed in CRC cells, and the expression level in T cells and DCs is very low.
How does miR-424 in cancer cells affect T cells and DCs? The strange phenomenon that MiR-424 reduced the expression of CD28 and CD80 on the surface of T cells and DCs led researchers to speculate that the lower expression of CD28 and CD80 in infiltrating T cells and DCs was caused by miR-424 secreted by CRC cells.
In order to confirm the above conjecture, the researchers first found that the extracellular vesicles (TEVs) secreted by CRC cancer cells are indeed rich in miR-424, and that tumor-infiltrating T cells and DCs cells can ingest TEVs containing miR-424 secreted by CRC.
And cause its CD28 and CD80 expression to decrease.
As we all know, extracellular vesicles (EVs) are lipid bilayer spheres released by cells that are encapsulated with DNA, RNA, lipids, cytoplasm and cell membrane proteins.
A large number of studies have shown that EVs are important mediators of cell-to-cell communication and are involved in a variety of physiological and pathological processes such as immune response, growth and development, metabolism and heart disease, neurodegeneration, and tumors [6].
Since miRNA-424 is the crux of the problem, can inhibiting miRNA-424 in CRC-derived EVs inhibit tumor growth? The researchers subcutaneously transplanted miRNA-424 knock-out CRC cells into mice.
Compared with the control group, tumors injected with miR-424 EVs grew faster, and the expression of CD28 and CD80 in the tumor infiltrating immune cells decreased.
The researchers also used Cd28-/-, Cd80/86-/- and other immunodeficient mice to verify that the tumor-promoting effect of miR-424 depends on the CD28-CD80/86 costimulatory signal.
Subsequent studies also found that inhibiting the expression of miR-424 in CRC cells changed the tumor microenvironment: In addition to the increased expression of CD28 and CD80 in infiltrating T cells and DCs cells, the amount of immune cell infiltration and IL-2 production were also enhanced.
As a result, the therapeutic effect of anti-PD-1/CTLA-4 drugs on advanced tumors is naturally improved.
Since TEVs containing miR-424 have immunosuppressive effects, after miR-424 is removed from TEVs, can TEVs produce immunogenic anti-tumor responses that activate T cells? The researchers then injected EVs derived from CRC cells that did not contain miR-424 into mice and found that it activated the proliferation of tumor antigen-specific CD8+ T cells in peripheral lymphoid organs, indicating that the modified EVs are immunogenic.
In the cecal orthotopic CRC late-stage mouse model, the modified EVs combined with anti-PD-1/CTLA-4 drugs has a 50% higher survival rate than anti-PD-1/CTLA-4 drugs alone, and reduces metastases.
It shows that the modified EVs have certain clinical therapeutic significance.
All in all, the study shows that tumor-derived extracellular vesicles contain immunosuppressive molecules that help tumor cells to escape immune.
In ICBT treatment, keeping the costimulatory signaling pathway in an active state is as important as inhibiting the co-inhibitory signaling pathway.
Removal of immunosuppressive factors in tumor-derived EVs can eliminate their immunosuppressive effects, and can be used as an adjuvant for immunotherapy to improve treatment efficiency and establish a treatment strategy based on EVs.
References[1] Wei SC, Duffy CR, Allison JP.
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy.
Cancer Discov.
2018;8(9):1069-1086.
doi:10.
1158/2159-8290.
CD-18-0367[ 2] Hodi FS, O'Day SJ, McDermott DF, et al.
Improved survival with ipilimumab in patients with metastatic melanoma [published correction appears in N Engl J Med.
2010 Sep 23;363(13):1290].
N Engl J Med.
2010;363(8):711-723.
doi:10.
1056/NEJMoa1003466[3] Pitt JM, Vétizou M, Daillère R, et al.
Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors Immunity.
2016;44(6):1255-1269.
doi:10.
1016/j.
immuni.
2016.
06.
001[4] Zhao X, Yuan C, Wangmo D, Subramanian S.
Tumor secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumor specific T-cell responses [published online ahead of print, 2021 Apr 22.
Gastroenterology.
2021;S0016-5085(21)00660-0.
doi:10.
1053/j.
gastro.
2021.
04.
036[5] Krol J, Loedige I, Filipowicz W.
The widespread regulation of microRNA biogenesis, function and decay.
Nat Rev Genet.
2010;11(9):597-610.
doi:10.
1038/nrg2843[6] Kalluri R, LeBleu VS.
The biology, function, and biomedical applications of exosomes.
Science.
2020;367(6478):eaau6977.
doi :10.
1126/science.
aau6977 Responsible EditorBioTalker
