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Autophagy is a strictly regulated and stress-induced catabolic pathway, which mainly includes typical autophagy and atypical autophagy pathways (Figure 1).
Autophagy has been an important mechanism for research in many fields such as tumor biology and immunology.
The autophagy pathway in the tumor microenvironment (TME) can be regulated in different types of cells under different pressures, thereby inhibiting or promoting tumor progression.
In recent years, immunotherapy has achieved certain success by using the immune system to stimulate an anti-tumor immune response.
However, tumor cells evade tumor immunity by reducing immunogenicity, forming an immunosuppressive network, and suppressing immune responses.
Recent studies have shown that the autophagy pathway is involved in the survival and apoptosis, differentiation, activation, effector function and tumor metastasis of immune cell subsets.
At the same time, tumor autophagy can change tumor growth by regulating the immune response.
Therefore, understanding how autophagy is simultaneously involved in fine-tuning the function and survival of immune cells, tumor cells and stromal cells in TME, and systematically regulating the autophagy pathway to increase the response rate to tumors is a new research direction in recent years.
Figure 1.
Typical and atypical autophagy pathways.
Autophagy pathways in major immune cell subpopulations in TME.
In order to target autophagy pathways in cancer immunotherapy, study the biology of autophagy in major immune cell subpopulations Activity is crucial.
Recent studies have begun to evaluate the autophagy pathways of T cells and macrophages (Figure 2).
In TME, T cells rely on autophagy to support their survival and differentiation.
The basal level of autophagy in naive T cells maintains their quiescent state and protects them from apoptosis induced by mitochondrial reactive oxygen species.
The high levels of lactic acid in the tumor interfered with the autophagy of naive T cells and weakened the anti-tumor response of the mouse model.
Autophagy is essential to the integrity of mitochondria, which determines the differentiation of effector T cells through metabolic reprogramming.
The high level of arginase 2 (ARG2) expression in tumor infiltrating Treg cells can maintain its high level of autophagy.
The loss of autophagy in Treg cells converts its metabolism from oxidative phosphorylation to glycolysis of active mTORC1 and MYC, resulting in instability of FOXP3.
The increased apoptosis and functional defects of autophagy-deficient Treg cells help to enhance tumor resistance.
Tumor-associated macrophages (TAMs) use fatty acid microtubule-associated protein 1A/1B light chain 3 (LC3)-related phagocytosis (LAP) to degrade apoptotic cancer cells.
The LAP defect of TAMs leads to the release of mitochondrial DNA from apoptotic cancer cells, which induces type I interferon response through the cGAS stimulator (STING) pathway and anti-tumor activity of interferon genes.
Figure 2.
Autophagy pathways of T cells and macrophages Targeting autophagy to improve immune response Current studies have found that targeting autophagy pathways can reshape TME (Figure 3).
Tumor autophagy inhibition can up-regulate the production of Th1 chemokines and promote tumor infiltration of effector immune cells; autophagy can mediate potential tumor antigens and major histocompatibility complexes (MHC) in antigen-presenting cells (APC) Degradation of ingredients.
Inhibition of autophagy can enhance the response of anti-tumor T cells by improving the processing and presentation of antigens; autophagy can mediate the degradation of MHC class I and granzyme B, avoiding cytotoxic T lymphocytes (CTL)-mediated killing and natural Killer (NK) cell-mediated killing.
Inhibition of autophagy can lead to an increase in the level of MHC class I molecules on the cell surface and prevent the autophagic degradation of granzyme B, thereby allowing cell lysis; inhibiting autophagy can also improve the therapeutic effect of ICB.
Large doses of IL-2 treatment can cause systemic autophagy syndrome.
Inhibition of autophagy protects cancer patients from systemic damage and improves IL-2 treatment.
Figure 3.
Targeting autophagy reshapes TME.
In addition, autophagy regulation can also provide some benefits for cancer patients receiving CAR-T cell therapy.
Inhibition of autophagy may promote the transfer of CAR-T cells to tumors; in addition, CAR-T cells directly recognize antigens on the surface of tumor cells, which can be degraded by autophagy.
Therefore, inhibiting tumor autophagy may lead to increased antigen expression, thereby enhancing the tumor killing effect mediated by CAR-T cells; since autophagic cell death may be related to cytokine release syndrome, inhibiting autophagy can improve CAR-T cytokines Release the syndrome, thereby bringing clinical benefits to patients.
Clinical progress in targeting the autophagy pathway At present, autophagy inhibitors are mainly divided into early inhibitors for ULK1/ULK2 or Vps34 (sbi-0206965, 3MA and wortmannin) and late inhibitors for lysosomes, such as chloroquine (CQ) , Hydroxychloroquine (HCQ), bafilin A1 and monensin.
Current clinical studies have found that autophagy as a monotherapy cannot produce an effective response in cancer patients.
At present, a number of clinical trials have explored the anti-tumor effects of autophagy inhibitors in combination with different treatment methods.
Since targeted autophagy can reshape TME, targeted autophagy can potentially enhance immunotherapy.
Therefore, immunotherapy combined with autophagy suppression may be a promising treatment method.
Currently, clinical trials using HCQ combined with immunotherapy are underway to treat patients with different types of cancer (Figure 4).
Figure 4.
Summary of clinical trials of HCQ combined with immunotherapy It is important to understand the multi-level relationship between autophagy pathways and tumor immune response.
We expect that autophagy modulators can enhance the immunogenicity and antigen presentation of tumors, improve the survival and function of tumor-infiltrating T cells, and may invalidate the immunosuppressive network in TME.
Using the autophagy pathway as a target to improve the effect of immunotherapy will be a promising and promising field, and it is expected to see patients benefit in the future.
References 1.
Autophagy in tumor immunity and therapy 2.
Diverse cellular roles of autophagy 3.
Targeting autophagy in cancer: recent advances and future directions.
4.
Autophagy and autophagy related proteins in cancer.
Copyright statement welcome personal forwarding and sharing.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Biopharmaceutical Editor" in a prominent position.
Autophagy has been an important mechanism for research in many fields such as tumor biology and immunology.
The autophagy pathway in the tumor microenvironment (TME) can be regulated in different types of cells under different pressures, thereby inhibiting or promoting tumor progression.
In recent years, immunotherapy has achieved certain success by using the immune system to stimulate an anti-tumor immune response.
However, tumor cells evade tumor immunity by reducing immunogenicity, forming an immunosuppressive network, and suppressing immune responses.
Recent studies have shown that the autophagy pathway is involved in the survival and apoptosis, differentiation, activation, effector function and tumor metastasis of immune cell subsets.
At the same time, tumor autophagy can change tumor growth by regulating the immune response.
Therefore, understanding how autophagy is simultaneously involved in fine-tuning the function and survival of immune cells, tumor cells and stromal cells in TME, and systematically regulating the autophagy pathway to increase the response rate to tumors is a new research direction in recent years.
Figure 1.
Typical and atypical autophagy pathways.
Autophagy pathways in major immune cell subpopulations in TME.
In order to target autophagy pathways in cancer immunotherapy, study the biology of autophagy in major immune cell subpopulations Activity is crucial.
Recent studies have begun to evaluate the autophagy pathways of T cells and macrophages (Figure 2).
In TME, T cells rely on autophagy to support their survival and differentiation.
The basal level of autophagy in naive T cells maintains their quiescent state and protects them from apoptosis induced by mitochondrial reactive oxygen species.
The high levels of lactic acid in the tumor interfered with the autophagy of naive T cells and weakened the anti-tumor response of the mouse model.
Autophagy is essential to the integrity of mitochondria, which determines the differentiation of effector T cells through metabolic reprogramming.
The high level of arginase 2 (ARG2) expression in tumor infiltrating Treg cells can maintain its high level of autophagy.
The loss of autophagy in Treg cells converts its metabolism from oxidative phosphorylation to glycolysis of active mTORC1 and MYC, resulting in instability of FOXP3.
The increased apoptosis and functional defects of autophagy-deficient Treg cells help to enhance tumor resistance.
Tumor-associated macrophages (TAMs) use fatty acid microtubule-associated protein 1A/1B light chain 3 (LC3)-related phagocytosis (LAP) to degrade apoptotic cancer cells.
The LAP defect of TAMs leads to the release of mitochondrial DNA from apoptotic cancer cells, which induces type I interferon response through the cGAS stimulator (STING) pathway and anti-tumor activity of interferon genes.
Figure 2.
Autophagy pathways of T cells and macrophages Targeting autophagy to improve immune response Current studies have found that targeting autophagy pathways can reshape TME (Figure 3).
Tumor autophagy inhibition can up-regulate the production of Th1 chemokines and promote tumor infiltration of effector immune cells; autophagy can mediate potential tumor antigens and major histocompatibility complexes (MHC) in antigen-presenting cells (APC) Degradation of ingredients.
Inhibition of autophagy can enhance the response of anti-tumor T cells by improving the processing and presentation of antigens; autophagy can mediate the degradation of MHC class I and granzyme B, avoiding cytotoxic T lymphocytes (CTL)-mediated killing and natural Killer (NK) cell-mediated killing.
Inhibition of autophagy can lead to an increase in the level of MHC class I molecules on the cell surface and prevent the autophagic degradation of granzyme B, thereby allowing cell lysis; inhibiting autophagy can also improve the therapeutic effect of ICB.
Large doses of IL-2 treatment can cause systemic autophagy syndrome.
Inhibition of autophagy protects cancer patients from systemic damage and improves IL-2 treatment.
Figure 3.
Targeting autophagy reshapes TME.
In addition, autophagy regulation can also provide some benefits for cancer patients receiving CAR-T cell therapy.
Inhibition of autophagy may promote the transfer of CAR-T cells to tumors; in addition, CAR-T cells directly recognize antigens on the surface of tumor cells, which can be degraded by autophagy.
Therefore, inhibiting tumor autophagy may lead to increased antigen expression, thereby enhancing the tumor killing effect mediated by CAR-T cells; since autophagic cell death may be related to cytokine release syndrome, inhibiting autophagy can improve CAR-T cytokines Release the syndrome, thereby bringing clinical benefits to patients.
Clinical progress in targeting the autophagy pathway At present, autophagy inhibitors are mainly divided into early inhibitors for ULK1/ULK2 or Vps34 (sbi-0206965, 3MA and wortmannin) and late inhibitors for lysosomes, such as chloroquine (CQ) , Hydroxychloroquine (HCQ), bafilin A1 and monensin.
Current clinical studies have found that autophagy as a monotherapy cannot produce an effective response in cancer patients.
At present, a number of clinical trials have explored the anti-tumor effects of autophagy inhibitors in combination with different treatment methods.
Since targeted autophagy can reshape TME, targeted autophagy can potentially enhance immunotherapy.
Therefore, immunotherapy combined with autophagy suppression may be a promising treatment method.
Currently, clinical trials using HCQ combined with immunotherapy are underway to treat patients with different types of cancer (Figure 4).
Figure 4.
Summary of clinical trials of HCQ combined with immunotherapy It is important to understand the multi-level relationship between autophagy pathways and tumor immune response.
We expect that autophagy modulators can enhance the immunogenicity and antigen presentation of tumors, improve the survival and function of tumor-infiltrating T cells, and may invalidate the immunosuppressive network in TME.
Using the autophagy pathway as a target to improve the effect of immunotherapy will be a promising and promising field, and it is expected to see patients benefit in the future.
References 1.
Autophagy in tumor immunity and therapy 2.
Diverse cellular roles of autophagy 3.
Targeting autophagy in cancer: recent advances and future directions.
4.
Autophagy and autophagy related proteins in cancer.
Copyright statement welcome personal forwarding and sharing.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Biopharmaceutical Editor" in a prominent position.
