JITC: Huazhong University of Science and Technology team found a new way to enhance immunotherapy!

In the clinical treatment of lung cancer , immune checkpoint therapy has brought some hope to patients, but its overall response rate still needs to be improved
.

To improve efficacy, the researchers combined radiation therapy with immune checkpoint therapy

In the clinical treatment of lung cancer , immune checkpoint therapy has brought some hope to patients, but its overall response rate still needs to be improved

However, in practical applications, the combined effect of radiotherapy and immune checkpoint therapy is not satisfactory

Researchers have their sights set on epigenetic therapy

Since epigenetic therapy can improve the tumor microenvironment, can it be used as a good assistant for immune checkpoint therapy and radiotherapy?

The answer is yes
.

A recent study by Xu Shuangbing and Wu Gang's team from the Tumor Center of Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology showed that in the treatment of lung cancer, inhibition of lysine-specific demethylase 4C ( KDM4C ) can promote CXCL10 gene transcription, Enhances antitumor immunity mediated by CD8+ T cells .
Inhibition of KDM4C in combination with radiotherapy and immune checkpoint therapy can produce synergistic efficacy in the treatment of lung cancer .

The answer is yes

Previously, the team found that KDM4C is a regulator of radiosensitivity in lung cancer, and inhibition of KDM4C could reverse the resistance of lung cancer to radiotherapy in vitro and in vivo [5]
.

Since KDM4C can regulate the resistance of lung cancer cells to radiotherapy, does it also play a role in the anti-tumor immune response, and how do these roles occur?

Previously, the team found that KDM4C is a regulator of radiosensitivity in lung cancer, and inhibition of KDM4C could reverse the resistance of lung cancer to radiotherapy in vitro and in vivo [5]

The researchers first started with a mouse lung cancer LLC model

 Inhibits KDM4C and delays LLC tumor growth

 Inhibits KDM4C and delays LLC tumor growth

As we all know, CD8+ T cells are the " main force " in anti-tumor immunity.

The reduction of tumor volume means that tumor cells are cleared by immune cells, so researchers also observed the changes of CD8+ T cells in the tumor microenvironment .
Flow cytometry analysis found that inhibition of KDM4C increased tumor-infiltrating immune cells by nearly 50% .
In vitro experiments, inhibition of KDM4C also promoted the proliferation of CD8+ T cells, and the migration ability was also enhanced .

As we all know, CD8+ T cells are the " main force " in anti-tumor immunity.
The reduction of tumor volume means that tumor cells are cleared by immune cells, so researchers also observed the changes of CD8+ T cells in the tumor microenvironment .
Flow cytometry analysis found that inhibition of KDM4C increased tumor-infiltrating immune cells by nearly 50% .
In vitro experiments, inhibition of KDM4C also promoted the proliferation of CD8+ T cells, and the migration ability was also enhanced .

Of course, the number of tumor-infiltrating immune cells is not enough, and the killing ability also has to keep up
.

Whether in vivo or in vitro, inhibition of KDM4C improved the killing ability and proliferation ability of tumor-infiltrating immune cells

Of course, the number of tumor-infiltrating immune cells is not enough, and the killing ability also has to keep up

After KDM4C inhibition , immune cell lethality is enhanced in LLC tumors and immune cells in the exhausted state are reduced 

After KDM4C inhibition , immune cell lethality is enhanced in LLC tumors and immune cells in the exhausted state are reduced 

Then, by what molecular mechanism does KDM4C control CD8+ T cells?

Then, by what molecular mechanism does KDM4C control CD8+ T cells?

Using RNA sequencing and bioinformatics analysis, the researchers found that six chemokine genes , including CXCL10 , were up-regulated after KDM4C inhibition in tumors .

In 2019 , Chen et al.
also found that CXCR3/CXCL10 -mediated T cell recruitment promoted the anti-tumor effect of chemoradiotherapy combined with anti- PD-1 antibody therapy [6] .

Using RNA sequencing and bioinformatics analysis, the researchers found that six chemokine genes , including CXCL10 , were up-regulated after bioinformatic KDM4C inhibition in tumors .
In 2019 , Chen et al.
also found that CXCR3/CXCL10 -mediated T cell recruitment promoted the anti-tumor effect of chemoradiotherapy combined with anti- PD-1 antibody therapy [6] .

Based on this, the researchers speculated that CXCL10 may be a key downstream candidate molecule of KDM4C .
The results of ChIP-PCR experiments showed that H3K36me3 protein was enriched in the promoter region of CXCL10 gene in tumor cells treated with KDM4C inhibitor SD70 .
H3K36me3 represents the triple methylation of lysine 36 on histone H3, which is usually associated with the activation of gene transcription .
Inhibition of KDM4C achieves epigenetic reprogramming in tumors, H3K36me3 will not be demethylated to H3K36me2 , and H3K36me3 can be abundantly enriched in the promoter region of CXCL10 gene, which promotes the up -regulation of CXCL10 gene expression .

Based on this, the researchers speculated that CXCL10 may be a key downstream candidate molecule of KDM4C .
The results of ChIP-PCR experiments showed that H3K36me3 protein was enriched in the promoter region of CXCL10 gene in tumor cells treated with KDM4C inhibitor SD70 .
H3K36me3 represents the triple methylation of lysine 36 on histone H3, which is usually associated with the activation of gene transcription .
Inhibition of KDM4C achieves epigenetic reprogramming in tumors, H3K36me3 will not be demethylated to H3K36me2 , and H3K36me3 can be abundantly enriched in the promoter region of CXCL10 gene, which promotes the up -regulation of CXCL10 gene expression .

To further confirm the role of CXCL10 in anti-tumor immunity, the researchers established a mouse lung cancer LLC model
.
Tumor growth was slowed after treatment with SD70 in tumor -bearing mice .
However, the tendency of SD70 to slow tumor growth disappeared after administration of the anti- CXCL10 antibody .
Flow cytometry analysis showed that after administration of SD70 and anti- CXCL10 antibodies, compared with SD70 alone treatment group, tumor-infiltrating immune cells decreased, and the killing ability of immune cells decreased .
This indicates that inhibition of KDM4C can promote anti-tumor immunity against lung cancer, and this effect is dependent on CXCL10 .

To further confirm the role of CXCL10 in anti-tumor immunity, the researchers established a mouse lung cancer LLC model
.
Tumor growth was slowed after treatment with SD70 in tumor -bearing mice .
However, the tendency of SD70 to slow tumor growth disappeared after administration of the anti- CXCL10 antibody .
Flow cytometry analysis showed that after administration of SD70 and anti- CXCL10 antibodies, compared with SD70 alone treatment group, tumor-infiltrating immune cells decreased, and the killing ability of immune cells decreased .
This indicates that inhibition of KDM4C can promote anti-tumor immunity against lung cancer, and this effect is dependent on CXCL10 .

Enhanced antitumor immunity is mediated by CXCL10 after inhibition of KDM4C

Enhanced antitumor immunity is mediated by CXCL10 after inhibition of KDM4C

Now that the efficacy and mechanism of inhibiting KDM4C were known , the researchers began to wonder whether it could be used in combination with other therapies to further enhance the anti-tumor effect
.
If the inhibition of KDM4C can promote the infiltration of CD8+ T cells, can the combination of KDM4C inhibitor and radiotherapy and immune checkpoint therapy produce a synergistic effect?

Now that the efficacy and mechanism of inhibiting KDM4C were known , the researchers began to wonder whether it could be used in combination with other therapies to further enhance the anti-tumor effect
.
If the inhibition of KDM4C can promote the infiltration of CD8+ T cells, can the combination of KDM4C inhibitor and radiotherapy and immune checkpoint therapy produce a synergistic effect?

Satisfyingly, in the mouse lung cancer LLC model, the combination of KDM4C inhibitor with 8Gy*3 radiation therapy and immune checkpoint therapy anti- PD-L1 antibody, the three " strong generals " shot, realized tumor growth.
The survival rate of tumor-bearing mice was also improved
.

Satisfyingly, in the mouse lung cancer LLC model, the combination of KDM4C inhibitor with 8Gy*3 radiation therapy and immune checkpoint therapy anti- PD-L1 antibody, the three " strong generals " shot, realized tumor growth.
The survival rate of tumor-bearing mice was also improved
.

Combination of radiotherapy, immune checkpoint therapy and SD70 inhibits tumor growth and prolongs survival in mice 

Combination of radiotherapy, immune checkpoint therapy and SD70 inhibits tumor growth and prolongs survival in mice 

It is worth mentioning that the researchers also confirmed the safety of the combination therapy.
The results of HE staining showed that the heart, liver, spleen and other organs of the mice in the combination therapy group were not seriously damaged
.
In addition, the biochemical analysis of the peripheral blood of the mice in each group also showed that in the control group and the combined treatment group, the liver and kidney function, cardiovascular function and pancreatic function of the treatment group were not significantly abnormal
.

It is worth mentioning that the researchers also confirmed the safety of the combination therapy.
The results of HE staining showed that the heart, liver, spleen and other organs of the mice in the combination therapy group were not seriously damaged
.
In addition, the biochemical analysis of the peripheral blood of the mice in each group also showed that in the control group and the combined treatment group, the liver and kidney function, cardiovascular function and pancreatic function of the treatment group were not significantly abnormal
.
Blood vessel

So far, through these studies, Xu Shuangbing and Wu Gang's team believe that inhibiting KDM4C can promote the aggregation of H3K36me3 in the promoter region of CXCL10 gene and up-regulate the expression of CXCL10 gene, thereby enhancing the killing effect of CD8+ T cells on lung cancer tumor cells .
The use of KDM4C inhibitors can promote immune cell infiltration, improve the tumor microenvironment , and heat up " cold " tumors, while its combination with anti- PD-L1 antibodies and radiation therapy can achieve effective sensitization with manageable side effects.
to achieve better anti-tumor effect .

So far, through these studies, Xu Shuangbing and Wu Gang's team believe that inhibiting KDM4C can promote the aggregation of H3K36me3 in the promoter region of CXCL10 gene and up-regulate the expression of CXCL10 gene, thereby enhancing the killing effect of CD8+ T cells on lung cancer tumor cells .
The use of KDM4C inhibitors can promote immune cell infiltration, improve the tumor microenvironment , and heat up " cold " tumors, while its combination with anti- PD-L1 antibodies and radiation therapy can achieve effective sensitization with manageable side effects.
to achieve better anti-tumor effect .

 Mechanism diagram

 Mechanism diagram

In conclusion, this study revealed the negative role of demethylase KDM4C in anti-tumor immunity of lung cancer, suggesting that inhibition of enzymes involved in tumor cell epigenetic modification may be a potential clinical adjuvant therapy strategy .

In conclusion, this study revealed the negative role of demethylase KDM4C in anti-tumor immunity of lung cancer, suggesting that inhibition of enzymes involved in tumor cell epigenetic modification may be a potential clinical adjuvant therapy strategy .

Some epigenetic therapies can reprogram the epigenome of cancer cells to disrupt the proliferation or invasion of cancer cells and achieve effective control of tumor growth
.
In the past decade, researchers have also discovered that epigenetic therapy can also regulate immune cells in the tumor microenvironment, thereby promoting the recognition and killing of tumor cells by the immune system.
A more potent immune response [7]
.
 

Some epigenetic therapies can reprogram the epigenome of cancer cells to disrupt the proliferation or invasion of cancer cells and achieve effective control of tumor growth
.
In the past decade, researchers have also discovered that epigenetic therapy can also regulate immune cells in the tumor microenvironment, thereby promoting the recognition and killing of tumor cells by the immune system.
A more potent immune response [7]
.
 

At present, epigenetic therapy has produced certain clinical effects.
If it can be better combined with radiotherapy, immune checkpoint therapy and even other therapies, it will bring more surprises to lung cancer patients and even other cancer patients.

.

At present, epigenetic therapy has produced certain clinical effects.
If it can be better combined with radiotherapy, immune checkpoint therapy and even other therapies, it will bring more surprises to lung cancer patients and even other cancer patients.

.

references:

references:

[1] Bernstein MB, Krishnan S, Hodge JW, Chang JY.
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[2] Garcia-Martinez L, Zhang Y, Nakata Y, Chan HL, Morey L.
Epigenetic mechanisms in breast cancer therapy and resistance.
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[2] Garcia-Martinez L, Zhang Y, Nakata Y, Chan HL, Morey L.
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[3] Zebley CC, Gottschalk S, Youngblood B.
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[3] Zebley CC, Gottschalk S, Youngblood B.
Rewriting History: Epigenetic Reprogramming of CD8+ T Cell Differentiation to Enhance Immunotherapy.
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[4] Jie X, Chen Y, Zhao Y, et al.
Targeting KDM4C enhances CD8+ T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer.
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[4] Jie X, Chen Y, Zhao Y, et al.
Targeting KDM4C enhances CD8+ T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer.
J Immunother Cancer.
2022;10(2):e003716.

[5] Jie X, Fong WP, Zhou R, et al.
USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription.
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[5] Jie X, Fong WP, Zhou R, et al.
USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription.
Cell Death Differ.
2021;28(7):2095-2111.

[6] Luo R, Firat E, Gaedicke S, Guffart E, Watanabe T, Niedermann G.
Cisplatin Facilitates Radiation-Induced Abscopal Effects in Conjunction with PD-1 Checkpoint Blockade Through CXCR3/CXCL10-Mediated T-cell Recruitment.
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[6] Luo R, Firat E, Gaedicke S, Guffart E, Watanabe T, Niedermann G.
Cisplatin Facilitates Radiation-Induced Abscopal Effects in Conjunction with PD-1 Checkpoint Blockade Through CXCR3/CXCL10-Mediated T-cell Recruitment.
Clin Cancer Res .
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[7]Topper MJ, Vaz M, Marrone KA, Brahmer JR, Baylin SB.
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[7]Topper MJ, Vaz M, Marrone KA, Brahmer JR, Baylin SB.
The emerging role of epigenetic therapeutics in immuno-oncology.
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