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Just as the environment has a great influence on a person, the tumor microenvironment (TME) has a very important impact on tumor growth, metabolism, metastasis, etc.
, and even affects the therapeutic effect of anti-cancer drugs.
In recent years, researches on tumor therapy targeting components in the tumor microenvironment have gradually increased.
Let the editor take you to understand the complex and changeable tumor microenvironment and how to target the tumor microenvironment for anti-cancer treatment.
"Family members" in the tumor microenvironment The tumor microenvironment is very complex and contains a variety of cells and components.
1) Immune cells: T, B lymphocytes, tumor-associated macrophages (TAM), dendritic cells (DC), natural killer cells (NK), neutrophils, myeloid-derived inhibitory cells (MDSC), etc.
.
2) Stromal cells: cancer-associated fibroblasts (CAF), pericytes, mesenchymal stromal cells, etc.
3) Extracellular matrix (ECM) and other secreted molecules: growth factors, cytokines, chemokines and extracellular vesicles (EV), etc.
4) Blood and lymphatic vascular network.
Tumors often use cells and molecules in the microenvironment to maintain an immunosuppressive microenvironment so that the immune system cannot eliminate them.
To destroy tumor cells, it is often necessary to start with the tumor microenvironment.
Figure 1.
"Family members" in the tumor microenvironment target each component of the tumor microenvironment-"divide and conquer" different cell subgroups in the tumor microenvironment have different functions and affect tumor development through multiple mechanisms.
Targeting different cell subgroups requires a variety of strategies to transform the immunosuppressive microenvironment into a microenvironment that is not conducive to tumor growth, and to control tumor growth.
1.
T cells T cells, especially killer T cells, can be said to be the mainstay of anti-tumor immunity. At present, there are two approaches to immunotherapy targeting T cells.
One is to enhance the anti-tumor ability of T cells by suppressing immune checkpoints, which is often mentioned PD-1/PD-L1/CTLA-4 inhibitor therapy.
The second is to enhance its anti-tumor effect by strengthening and transforming T cells (chimeric antigen receptor CAR-T, or gene editing of T cell receptors).
Today we mainly introduce the first way.
1) PD-1/PD-L1 inhibitor.
This may be the most well-known immunotherapy.
PD-1 is the "brake" mechanism of killer T cells.
The killer is too powerful to be unregulated, so as not to accidentally injure itself.
And it is this point that is used by cunning tumor cells: killer T cells originally received instructions to perform their tasks; but tumor cells use their own PD-L1 to bind PD-1 on the surface of T cells and "seal" it.
PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, remove the seal of killer cells, so that they can perform their tasks again and destroy tumor cells.
Figure 2.
The mechanism of action of PD-1/PD-L1 inhibitors At present, many PD-1/PD-L1 inhibitor drugs have been approved for clinical treatment.
2) CTLA4 inhibitors are another way to enhance the ability of T cells to kill tumor cells.
The use of monoclonal antibody ipilimumab for CTLA4 blockade has benefited cancer patients, especially melanoma patients, in nearly 2,000 clinical trials.
3) Other targets.
In addition to PD1/PD-L1/CTLA4, there are many immune targets.
Inhibiting them can activate T cells and help kill tumors, such as LAG3, TIM3, TIGIT, etc.
, their high expression is related to poor prognosis.
Related inhibitors are also under development, and many early clinical trials have shown good results.
2.
Tumor-associated macrophages (TAMs) Macrophages are the scavengers of our body, which can swallow and remove cell debris, maintain tissue homeostasis and resist infection. In the tumor microenvironment, macrophages often "blacken", helping tumors grow and metastasize, and evade killer cells.
Such "melanized" macrophages are called tumor-associated macrophages (TAMs).
Clinical data shows that the more TAMs, the worse the prognosis of patients, and TAMs are also related to treatment resistance.
This indicates that TAMs can be used as prognostic biomarkers and therapeutic targets.
The current drugs targeting TAMs are mainly to remove TAMs in the tumor microenvironment, or to block the inhibitory function of TAMs.
In fact, the targeted therapy of macrophages can not only block the help of TAM on cancer cells, but also increase the antigen presentation to killer T cells, thereby enhancing the anti-tumor efficacy.
Targeted therapy studies of macrophages include: 1) CSF1R inhibitor, delete TAMs in TME and/or change its function; 2) CCL2 or CCR2 inhibitor, block monocyte recruitment to TME and reduce the number of TAMs ; 3) CD47/SIRPα complex antagonist, inhibits CD47-mediated "don't eat me" signal, and enhances the phagocytosis of TAM on cancer cells; 4) costimulatory molecules such as CD40, CD40 expressed on TAMs is mediated by T cells The addition of CD40 can enhance the activation of T cells; 5) Inhibitors of protein PI3Kγ and TREM2.
Both PI3Kγ and TREM2 are important regulators of TAMs' immunosuppressive function.
Inhibiting them can stop TAMs.
Blackening".
3.
Dendritic cells Dendritic cells are the signal soldiers and trainers of the immune system.
They can ingest and process antigens such as tumors or pathogens, present the antigens to T cells, and activate them.
Dendritic cells can help induce strong and durable anti-tumor immunity: 1) Migration ability between lymphoid organs and non-lymphoid organs; 2) Cross-presenting tumor-associated antigens to killer T cells, enhancing the anti-tumor effect; 3 ) Release chemokines and cytokines to regulate the overall immune response and T cell recruitment.
In fact, the increase of dendritic cells in the tumor microenvironment is correlated with the better prognosis of patients with ovarian cancer, lung cancer and breast cancer.
Therefore, dendritic cells can be used as a promising target for tumor immunotherapy.
However, tumors also interfere with the function of dendritic cells through a variety of mechanisms.
Current researches targeting dendritic cells are aimed at increasing the number of dendritic cells in tumors and restoring their functions.
The current strategies are: 1) Use FLT3L to induce the expansion and survival of dendritic cells in vivo.
FLT3L is necessary for the differentiation and survival of dendritic cells.
2) Through GM-CSF to regulate the activity of dendritic cells, GM-CSF can promote the proliferation, maturation and survival of dendritic cells.
3) Through the dendritic cell vaccine, the ability to present tumor antigens is strengthened, and the recruitment of T cells and NK cells is promoted to strengthen anti-tumor immunity.
4.
Targeting tumor-related mesenchymal cells and vascular system.
The excessive proliferation of cells in tumors requires additional blood vessels to transport oxygen and nutrients.
Therefore, anti-angiogenic drugs can be used to target tumor vasculature to fight cancer, such as vascular endothelial growth factor.
(Vascular endothelial growth factor, VEGF) inhibitor bevacizumab, small molecule multi-target receptor tyrosine kinase inhibitor sunitinib, apatinib and anlotinib, etc.
The extracellular matrix is composed of a variety of macromolecules, including collagen, glycoprotein, elastin, fibrin, and proteoglycan, which are secreted by cells into the extracellular space.
Compared with healthy tissues, the coverage, density and stiffness of the extracellular matrix of tumors have increased.
The extracellular matrix of tumors not only provides structural support for tumor growth, but also regulates various cells in the tumor and microenvironment.
For example, the increase in tissue stiffness can promote tumor cell transformation, which is related to tumor invasion and metastasis.
Related targeted drugs mainly degrade extracellular matrix (such as collagenase or hyaluronidase), or inhibit the synthesis of key factors of extracellular matrix (inhibit LOX enzyme).
Summary Targeted therapy of tumor microenvironment has always been considered a very promising anti-cancer strategy.
The clinical approval of drugs targeting the vascular system, immune checkpoint inhibitors, and T cell therapy has benefited many patients.
However, because of the complexity and variability of the tumor microenvironment, a single target may not be sufficient to control the progress of the tumor.
The combined treatment of multiple methods can exert a better therapeutic effect, thereby benefiting more patients.
Join the Cancer Degree App, communicate with patients, and get the latest anti-cancer progress.
References Bejarano, L.
, Jordāo, MJC & Joyce, JA Therapeutic Targeting of the Tumor Microenvironment.
Cancer Discov.
11, 933–959 (2021).
Click below to learn more about the past review of clinical trial projects
, and even affects the therapeutic effect of anti-cancer drugs.
In recent years, researches on tumor therapy targeting components in the tumor microenvironment have gradually increased.
Let the editor take you to understand the complex and changeable tumor microenvironment and how to target the tumor microenvironment for anti-cancer treatment.
"Family members" in the tumor microenvironment The tumor microenvironment is very complex and contains a variety of cells and components.
1) Immune cells: T, B lymphocytes, tumor-associated macrophages (TAM), dendritic cells (DC), natural killer cells (NK), neutrophils, myeloid-derived inhibitory cells (MDSC), etc.
.
2) Stromal cells: cancer-associated fibroblasts (CAF), pericytes, mesenchymal stromal cells, etc.
3) Extracellular matrix (ECM) and other secreted molecules: growth factors, cytokines, chemokines and extracellular vesicles (EV), etc.
4) Blood and lymphatic vascular network.
Tumors often use cells and molecules in the microenvironment to maintain an immunosuppressive microenvironment so that the immune system cannot eliminate them.
To destroy tumor cells, it is often necessary to start with the tumor microenvironment.
Figure 1.
"Family members" in the tumor microenvironment target each component of the tumor microenvironment-"divide and conquer" different cell subgroups in the tumor microenvironment have different functions and affect tumor development through multiple mechanisms.
Targeting different cell subgroups requires a variety of strategies to transform the immunosuppressive microenvironment into a microenvironment that is not conducive to tumor growth, and to control tumor growth.
1.
T cells T cells, especially killer T cells, can be said to be the mainstay of anti-tumor immunity. At present, there are two approaches to immunotherapy targeting T cells.
One is to enhance the anti-tumor ability of T cells by suppressing immune checkpoints, which is often mentioned PD-1/PD-L1/CTLA-4 inhibitor therapy.
The second is to enhance its anti-tumor effect by strengthening and transforming T cells (chimeric antigen receptor CAR-T, or gene editing of T cell receptors).
Today we mainly introduce the first way.
1) PD-1/PD-L1 inhibitor.
This may be the most well-known immunotherapy.
PD-1 is the "brake" mechanism of killer T cells.
The killer is too powerful to be unregulated, so as not to accidentally injure itself.
And it is this point that is used by cunning tumor cells: killer T cells originally received instructions to perform their tasks; but tumor cells use their own PD-L1 to bind PD-1 on the surface of T cells and "seal" it.
PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, remove the seal of killer cells, so that they can perform their tasks again and destroy tumor cells.
Figure 2.
The mechanism of action of PD-1/PD-L1 inhibitors At present, many PD-1/PD-L1 inhibitor drugs have been approved for clinical treatment.
2) CTLA4 inhibitors are another way to enhance the ability of T cells to kill tumor cells.
The use of monoclonal antibody ipilimumab for CTLA4 blockade has benefited cancer patients, especially melanoma patients, in nearly 2,000 clinical trials.
3) Other targets.
In addition to PD1/PD-L1/CTLA4, there are many immune targets.
Inhibiting them can activate T cells and help kill tumors, such as LAG3, TIM3, TIGIT, etc.
, their high expression is related to poor prognosis.
Related inhibitors are also under development, and many early clinical trials have shown good results.
2.
Tumor-associated macrophages (TAMs) Macrophages are the scavengers of our body, which can swallow and remove cell debris, maintain tissue homeostasis and resist infection. In the tumor microenvironment, macrophages often "blacken", helping tumors grow and metastasize, and evade killer cells.
Such "melanized" macrophages are called tumor-associated macrophages (TAMs).
Clinical data shows that the more TAMs, the worse the prognosis of patients, and TAMs are also related to treatment resistance.
This indicates that TAMs can be used as prognostic biomarkers and therapeutic targets.
The current drugs targeting TAMs are mainly to remove TAMs in the tumor microenvironment, or to block the inhibitory function of TAMs.
In fact, the targeted therapy of macrophages can not only block the help of TAM on cancer cells, but also increase the antigen presentation to killer T cells, thereby enhancing the anti-tumor efficacy.
Targeted therapy studies of macrophages include: 1) CSF1R inhibitor, delete TAMs in TME and/or change its function; 2) CCL2 or CCR2 inhibitor, block monocyte recruitment to TME and reduce the number of TAMs ; 3) CD47/SIRPα complex antagonist, inhibits CD47-mediated "don't eat me" signal, and enhances the phagocytosis of TAM on cancer cells; 4) costimulatory molecules such as CD40, CD40 expressed on TAMs is mediated by T cells The addition of CD40 can enhance the activation of T cells; 5) Inhibitors of protein PI3Kγ and TREM2.
Both PI3Kγ and TREM2 are important regulators of TAMs' immunosuppressive function.
Inhibiting them can stop TAMs.
Blackening".
3.
Dendritic cells Dendritic cells are the signal soldiers and trainers of the immune system.
They can ingest and process antigens such as tumors or pathogens, present the antigens to T cells, and activate them.
Dendritic cells can help induce strong and durable anti-tumor immunity: 1) Migration ability between lymphoid organs and non-lymphoid organs; 2) Cross-presenting tumor-associated antigens to killer T cells, enhancing the anti-tumor effect; 3 ) Release chemokines and cytokines to regulate the overall immune response and T cell recruitment.
In fact, the increase of dendritic cells in the tumor microenvironment is correlated with the better prognosis of patients with ovarian cancer, lung cancer and breast cancer.
Therefore, dendritic cells can be used as a promising target for tumor immunotherapy.
However, tumors also interfere with the function of dendritic cells through a variety of mechanisms.
Current researches targeting dendritic cells are aimed at increasing the number of dendritic cells in tumors and restoring their functions.
The current strategies are: 1) Use FLT3L to induce the expansion and survival of dendritic cells in vivo.
FLT3L is necessary for the differentiation and survival of dendritic cells.
2) Through GM-CSF to regulate the activity of dendritic cells, GM-CSF can promote the proliferation, maturation and survival of dendritic cells.
3) Through the dendritic cell vaccine, the ability to present tumor antigens is strengthened, and the recruitment of T cells and NK cells is promoted to strengthen anti-tumor immunity.
4.
Targeting tumor-related mesenchymal cells and vascular system.
The excessive proliferation of cells in tumors requires additional blood vessels to transport oxygen and nutrients.
Therefore, anti-angiogenic drugs can be used to target tumor vasculature to fight cancer, such as vascular endothelial growth factor.
(Vascular endothelial growth factor, VEGF) inhibitor bevacizumab, small molecule multi-target receptor tyrosine kinase inhibitor sunitinib, apatinib and anlotinib, etc.
The extracellular matrix is composed of a variety of macromolecules, including collagen, glycoprotein, elastin, fibrin, and proteoglycan, which are secreted by cells into the extracellular space.
Compared with healthy tissues, the coverage, density and stiffness of the extracellular matrix of tumors have increased.
The extracellular matrix of tumors not only provides structural support for tumor growth, but also regulates various cells in the tumor and microenvironment.
For example, the increase in tissue stiffness can promote tumor cell transformation, which is related to tumor invasion and metastasis.
Related targeted drugs mainly degrade extracellular matrix (such as collagenase or hyaluronidase), or inhibit the synthesis of key factors of extracellular matrix (inhibit LOX enzyme).
Summary Targeted therapy of tumor microenvironment has always been considered a very promising anti-cancer strategy.
The clinical approval of drugs targeting the vascular system, immune checkpoint inhibitors, and T cell therapy has benefited many patients.
However, because of the complexity and variability of the tumor microenvironment, a single target may not be sufficient to control the progress of the tumor.
The combined treatment of multiple methods can exert a better therapeutic effect, thereby benefiting more patients.
Join the Cancer Degree App, communicate with patients, and get the latest anti-cancer progress.
References Bejarano, L.
, Jordāo, MJC & Joyce, JA Therapeutic Targeting of the Tumor Microenvironment.
Cancer Discov.
11, 933–959 (2021).
Click below to learn more about the past review of clinical trial projects
