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How does autophagy play a role in tumor immunity and treatment?
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How does autophagy play a role in tumor immunity and treatment?
Autophagy is a regulatory mechanism that removes unnecessary or dysfunctional cellular components and recovers metabolic substrates.
In response to the stress signals in the tumor microenvironment, the autophagy pathways in tumor cells and immune cells are changed, which has different effects on tumor progression, immunity and treatment.
Recent studies have shown that the autophagy pathway is involved in the survival and apoptosis of immune cell subsets, differentiation, activation, effector functions, and transport to tumors.
At the same time, tumor autophagy can change tumor growth by regulating the immune response.
In addition, by combining immune checkpoint therapy with autophagy inhibitors, the tumor-promoting effects of autophagy can be eliminated.
Therefore, autophagy is a complex but promising target in cancer treatment.
Tumor cell autophagy
The tumor microenvironment ( TME ) plays a key role in cancer progression, metastasis, and treatment resistance. In TME, autophagy in tumor cells can be induced by intracellular and extracellular stress signals, including metabolic stress, hypoxia, redox stress and immune signals.
Insufficient nutrition ingested by TME will affect the metabolic mechanism and cause metabolic stress in the cell.
In response to metabolic stress, tumor cells rebuild their own metabolic pathways by up-regulating nutrient transporters and activating autophagy.
In terms of mechanism, 5′-AMP-activated protein kinase ( AMPK ) and mTOR complex 1 ( mTORC1 ) are two opposite regulatory kinases, which change the induction of autophagy in the case of nutrient deficiency.
As an AMP sensor, AMPK is activated by an increase in the ratio of AMP and ATP, while the activity of mTORC1 decreases due to lack of amino acids.
This leads to phosphorylation of the target in the complex before the initiation of autophagy, thereby initiating autophagy.
Hypoxia is a characteristic of solid tumors.
Hypoxia leads to inhibition of mitochondrial oxidative phosphorylation, an increase in the ratio of AMP to ATP, AMPK activation, and hypoxia also inhibits mTOR signaling.
In addition, hypoxia leads to the activation of activated transcription factor 4 ( ATF4 ), thereby up-regulating the expression of LC3B and autophagy-related protein 5 ( ATG5 ) and maintaining high levels of autophagy.
Oxidative stress reflects the imbalance between free radicals and antioxidants. Reactive oxygen species ( ROS ) are produced in cells through oxygen metabolism and other processes.
Excessive reactive oxygen species may increase the risk of DNA damage and promote the occurrence of tumors.
As a response to elevated ROS, the telangiectatic ataxia mutation ( ATM ) activates the TSC2 tumor suppressor through the hepatic kinase B1 ( LKB1 ) and AMPK metabolic pathways in the cytoplasm to inhibit mTORC1 and induce autophagy.
Oxidative stress can also promote autophagy through up-regulation of p62/SQSTM1 mediated by NF-κB.
Immune signals can regulate the autophagy pathway in TME.
Damage-related molecular patterns ( DAMP ) and cytokines are the main mediators that regulate autophagy.
Extracellular DAMP signals are sensed by extracellular or intracellular pattern recognition receptors, such as Toll-like receptors ( TLR ).
When various TLRs recognize DAMP and activate downstream signals, autophagy is induced.
In addition, in Drosophila, cytokines such as TNF and IL-6-like signals can activate autophagy, thereby promoting early tumor growth and invasion.
TGF-β increases the transcription level of BECN1, ATG5 and ATG7 through SMAD-dependent and SMAD-independent pathways, and activates autophagy, which can delay the apoptosis of human hepatocellular carcinoma and breast cancer cells in vitro.
Autophagy-mediated immune evasion
Evasion of anti-tumor immune response is an important survival strategy for various tumors.
Recent evidence indicates that autophagy plays an important role in tumor immune evasion. Studies have found that the down-regulation of MHC class I molecules in pancreatic ductal adenocarcinoma ( PDAC ) is mediated by selective autophagy degradation, inhibiting autophagy to release a strong anti-tumor immune response.
On the other hand, MDSCs play an immunosuppressive effect in TME.
Studies have shown that autophagy in MDSC is a key mechanism for suppressing the anti-tumor immune activity of melanoma.
Autophagy in MDSC immune cells is the center of degrading MHC class II molecules, preventing the initiation and activation of anti-tumor T cells.
Autophagy and resistance
As a mechanism for ( cancer ) cells to respond to threatening stressors, autophagy is considered to be an important mechanism for treatment resistance in cancer treatment.
There is evidence that the resistance of tumor cells to cisplatin is at least partially mediated by increased autophagy in ovarian cancer cell lines.
Similar evidence suggests that cisplatin, doxorubicin, and methotrexate overcome chemotherapy resistance by inhibiting autophagy in osteosarcoma.
Interestingly, for example, the interaction between cisplatin and autophagy is a continuum, and even in cells that are not resistant to certain chemotherapeutic drugs in vitro and in vivo, autophagy inhibitors, such as chloroquine ( CQ ) can also improve the treatment effect.
This has been confirmed in mouse models of adrenocortical carcinoma, colon cancer cell lines and 5-fluorouracil and temozolomide-induced cytotoxicity of glioma cells.
In addition, similar results have been achieved for antibody-based therapies.
For example, in trastuzumab-resistant breast cancer cells, autophagy inhibition using CQ resulted in almost complete tumor elimination.
Similarly, the use of CQ to inhibit autophagy can also effectively combat bevacizumab-induced autophagy of colorectal cancer cells and reduce tumor growth in mouse tumor models in vivo.
Research status of autophagy in tumor treatment
Autophagy inhibitors are divided into early inhibitors against ULK1/ULK2 or VPS34, such as SBI-0206965, 3MA, and wortmannin, and late inhibitors against lysosomes, such as CQ, hydroxychloroquine ( HCQ ), bafilomycin A1 And monensin, CQ and HCQ inhibit autophagosome degradation by interfering with lysosomal acidification.
However, in clinical trials, HCQ monotherapy failed to control tumor growth in patients with advanced pancreatic cancer.
At present, autophagy suppression is often combined with other cancer treatments to improve the therapeutic effect.
The high autophagy flux in cancer is associated with reduced chemotherapy response and is associated with the low survival rate of cancer patients.
Preclinical studies have shown that inhibiting autophagy can overcome chemotherapy resistance in NSCLC, bladder cancer, thyroid cancer and pancreatic cancer.
In addition, the results of some studies indicate that autophagy inhibition may have a synergistic effect with the inhibition of MEK-ERK signaling.
An early phase II study in 2014 used HCQ monotherapy to treat patients with metastatic pancreatic cancer who had previously been treated by other methods, and the primary endpoint was a two-month progression-free survival.
As a result, the level of autophagy in different patients decreased to varying degrees, but the primary endpoint did not improve significantly.
Another study combining HCQ, gemcitabine, and nab paclitaxel in the treatment of patients with advanced or metastatic pancreatic cancer also failed to prove a 12-month extension of overall survival.
However, it is important that patients using HCQ showed a significant and better response rate ( 38.2% vs. 21.1% ).
Autophagy plays a key role in protecting tumor cells from cell death caused by radiotherapy.
In breast cancer cells, radiation induces the expression of autophagy-related genes, accompanied by the accumulation of autophagosomes. Short-term inhibition of autophagy while radiotherapy can enhance the cytotoxicity of radiotherapy to drug-resistant cancer cells.
Similarly, hypoxia enhances the radioresistance of A549 lung cancer cells by inducing autophagy.
In glioblastoma, radiotherapy induces autophagy by increasing the expression of mammalian STE20-like protein kinase 4 ( MST4 ), which stimulates autophagy through phosphorylation of ATG4B.
The small molecule inhibitor NSC185058 ( targeting ATG4B ) combined with radiotherapy can impair the growth of intracranial xenografts of glioblastoma and prolong the survival time of treated mice.
Therefore, targeting tumor autophagy may enhance the efficacy of radiotherapy. In fact, in clinical trials of cancer patients, autophagy inhibitors have been combined with radiotherapy.
Utilizing the immune system is an important way to fight cancer. Inhibition of autophagy may impair system immunity, because autophagy involves the development of the immune system and the survival and function of effector T cells.
However, in preclinical models of melanoma and breast cancer, the systemic inhibition of autophagy by CQ in a short period of time did not impair T cell function.
The data suggests that the immune system may be tolerant to some degree of autophagy suppression.
However, given that autophagy can regulate tumor immune response, targeted autophagy can improve the efficacy of immunotherapy and overcome the resistance of immunotherapy.
For example, the use of inhibitors SB02024 or SAR405 to inhibit VPS34 kinase activity leads to increased levels of CCL5, CXCL10, and IFN-γ in TME, thereby increasing the level of NK cell and T cell tumor infiltration in melanoma and colorectal cancer models. In these models, VPS34 inhibition also reversed resistance to anti-PD1 or anti-PD-L1 therapy.
In addition, CQ therapy can block autophagy-mediated MHC class I degradation, and synergize with dual ICB therapy ( anti-PD1 and anti-CTLA4 antibodies ) to produce an enhanced anti-tumor immune response in mouse models of pancreatic cancer.
Therefore, targeted autophagy may enhance immunotherapy. Currently, clinical trials of HCQ combined with immunotherapy for the treatment of patients with different types of cancer are ongoing.
In addition, CAR-T cell therapy has achieved clinical success in the treatment of hematological tumors, but still has limited efficacy in the treatment of solid cancers.
Autophagy regulation may provide some benefits for cancer patients treated with CAR-T cells. As we all know, TME is a barrier to CAR-T cell infiltration and function in solid tumors.
In view of the fact that autophagy inhibition can reshape TME and promote the production of TH1 chemokines, autophagy inhibition can promote the transport of CAR-T cells to tumors.
The enhanced autophagy of T cells may support the adaptability and survival of T cells in TME. In addition, the inhibition of tumor autophagy may lead to increased antigen expression, thereby enhancing the tumor killing effect mediated by CAR-T cells.
Finally, autophagy inhibition may improve cytokine release syndrome and bring clinical benefits to patients. In general, the potential to inhibit autophagy to improve the effectiveness of immunotherapy is a promising area that is constantly being explored.
Autophagy is an important mechanism for research in many fields such as tumor biology and immunology.
In view of the fact that different factors in different cells in TME can induce autophagy, its induction and activation can promote or inhibit tumor progression.
Autophagy in T cell subsets may play a positive role in anti-tumor immune response, while functional autophagy in tumor cells may support tumor antigen presentation and recognition.
In this case, inhibiting autophagy may be harmful to anti-tumor immunity.
On the other hand, the autophagy pathway may be related to tumor cell survival, tumor antigen degradation, reduction of TH1 chemokines, enhancement of Treg cells and MDSC.
Therefore, cancer treatment methods that target autophagy as a system are challenging.
Therefore, in order to target the autophagy pathway in tumor immunotherapy, it is important to explore the biological activity of autophagy in the main immune cell subgroups.
Recent studies have begun to evaluate the autophagy pathways of T cells, macrophages, and dendritic cells.
Future work may be extended to B cells, NK cells and NKT cells. In addition, as cancer progresses, the pathway of autophagy will dynamically change in response to different stimuli in TME.
It is necessary to understand how autophagy participates in the function and survival of immune cells, tumor cells and stromal cells in TME at the same time.
Can ultimately enable cancer patients to obtain clinical benefits.
1.Autophagy in tumour immunity and therapy. NatRev Cancer. 2021 May; 21(5): 281–297.
2. Autophagy in Cancer Therapy-Molecular Mechanisms and Current Clinical Advances. Cancers (Basel). 2021 Nov8;13(21):5575.
How does autophagy play a role in tumor immunity and treatment?
(source:internet, reference only)