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iNature dendritic cells (DCs) are central to initiating and regulating innate and adaptive immunity in the tumor microenvironment
.
Therefore, a variety of vaccines targeting DC have been developed to improve cancer immunotherapy in numerous clinical trials
.
Targeted delivery of antigens and adjuvants to DCs in vivo represents an important approach for developing DC vaccines
.
However, the nonspecific activation of systemic DCs and the preparation of optimal immunodominant tumor antigens remain major challenges
.
On February 11, 2022, Wang Fubing, Zhongnan Hospital of Wuhan University, and Yuan Chunhui's team of Wuhan Women and Children's Health Care Center published online at Molecular Cancer (IF=27) entitled "Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer”, which loaded the immunogenic cell death (ICD) inducers human neutrophil elastase (ELANE) and Hiltonol (a TLR3 agonist) into engineered α-lactalbumin (α-LA) breast cancer-derived exosomes to form an in situ DC vaccine (HELA-Exos)
.
This study found that HELA-Exos has a strong ability to specifically induce ICD in breast cancer cells
.
Following HELA-Exo-induced ICD in cancer cells, adequate exposure to tumor antigens and Hiltonol in situ activates type 1 conventional DCs (cDC1s) and cross-prime tumor-reactive CD8+ T-cell responses, resulting in the development of immunogenicity in poorly immunogenic triple-negative breast cancer.
Efficient tumor suppression in mouse xenograft models of cancer (TNBC) and patient-derived tumor organoids
.
In conclusion, this study found that HELA-Exos exhibited potent antitumor activity in mouse models and human breast cancer organoids by promoting the activation of cDC1 in situ, thereby improving subsequent tumor-reactive CD8+ T cell responses
.
The strategy presented here holds promise for generating in situ DC-primed vaccines and can be extended to various types of cancer
.
As the most potent antigen-presenting cells (APCs), dendritic cells (DCs) are central to the initiation and regulation of innate and adaptive immunity in the tumor microenvironment (TME), with the ability to present tumor-associated antigens (TAAs) on MHC molecules ) and the ability to provide costimulatory/soluble factors to shape antitumor T cell responses
.
Therefore, in numerous clinical trials, a variety of DC-targeted vaccines have been developed to improve cancer immunotherapy
.
Targeted delivery of antigens and adjuvants to DCs in vivo is an important approach to enhance the antitumor effects of DCs
.
Compared to ex vivo generation, in vivo activation and mobilization of DCs allows for vaccine production on a larger scale and allows direct activation of native DC subsets at multiple sites in vivo
.
However, since DC-target receptors, such as DEC205 and DC-SIGN, are not exclusively expressed on tumor-infiltrating DCs, this strategy can also induce antigen-nonspecific activation of the immune system and potential side effects
.
Furthermore, another major challenge in implementing this strategy is the identification of the best immunodominant tumor antigens, such as TAA, TSA and even patient-specific neoantigens
.
Efforts to address these issues are critical to making DC vaccines clinically viable
.
The type of cell death induced in tumor cells affects their efficacy in inducing immunity
.
Immunogenic cell death (ICD) enhances tumor antigen exposure, promotes the release of immunostimulatory tumor cell contents, and facilitates DC uptake of dying tumor cells
.
In this context, ICDs have been approved for whole tumor lysate preparations for autologous DC vaccines
.
Therefore, induction of ICD in tumor cells would be an effective method to maintain adequate exposure of DCs to tumor antigens
.
On the other hand, DCs generally exhibit poor maturity in the TME and are therefore less effective at presenting tumor antigens
.
Adjuvants driving the activation of immunogenic DCs, in particular agonists of TLR3, are being actively studied
.
Administration of TLR3 agonists is highly effective in inducing type 1 conventional DC (cDC1) maturation, which is necessary for the induction of cellular immunity and has been associated with increased survival in patients with certain cancer types due to their efficient processing and crossover
.
Therefore, targeted delivery of ICD inducers and TLR3 agonists into tumor cells would be an ideal approach to activate tumor-infiltrating DCs in situ and avoid interactions in the immune milieu of other sites
.
In recent years, exosomes have attracted attention as drug delivery vehicles because of their low cytotoxicity, ability to maximize drug bioavailability, and excellent target homing specificity
.
The therapeutic potential of exosomes is demonstrated in their growing number of clinical trials for the treatment of chronic kidney disease, non-small cell lung cancer, colon cancer, type 1 diabetes and severe COVID-19
.
Notably, in a mouse model, the chemotherapeutic drug doxorubicin (Dox) was more stable when loaded in breast cancer-derived exosomes and accumulated in tumors more effectively than free Dox for therapy breast cancer
.
Therefore, tumor-derived exosomes (Texs) can be used as cell-free therapeutic vehicles to infiltrate the TME for in situ DC activation
.
Here, we developed and optimized a target-specific exosome formulation loaded with Hiltonol, a TLR3 agonist, and the ICD inducer, human neutrophil elastase (ELANE), to form a target-specific exosome formulation for breast cancer therapy.
In situ DC vaccine
.
Alpha-lactalbumin (α-LA), a breast-specific immunodominant protein expressed in most human breast cancers, is further enriched on the surface of exosomes as a specific tumor-homing protein to enhance Targeting ability and immunogenicity
.
In mouse models and patient-derived tumor organoids, these Hiltonol-ELANE-α-LA engineered exosomes (HELA-Exos) have a robust ability to accumulate in cancer cells after systemic administration, and are compatible with free Hiltonol has better therapeutic effect
.
Therefore, the combination of cell-free exosome-based TLR3 agonists with ICD inducers provides a powerful and novel therapeutic platform for designing DC vaccines for breast cancer
.
Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-022-01515-x
.
Therefore, a variety of vaccines targeting DC have been developed to improve cancer immunotherapy in numerous clinical trials
.
Targeted delivery of antigens and adjuvants to DCs in vivo represents an important approach for developing DC vaccines
.
However, the nonspecific activation of systemic DCs and the preparation of optimal immunodominant tumor antigens remain major challenges
.
On February 11, 2022, Wang Fubing, Zhongnan Hospital of Wuhan University, and Yuan Chunhui's team of Wuhan Women and Children's Health Care Center published online at Molecular Cancer (IF=27) entitled "Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer”, which loaded the immunogenic cell death (ICD) inducers human neutrophil elastase (ELANE) and Hiltonol (a TLR3 agonist) into engineered α-lactalbumin (α-LA) breast cancer-derived exosomes to form an in situ DC vaccine (HELA-Exos)
.
This study found that HELA-Exos has a strong ability to specifically induce ICD in breast cancer cells
.
Following HELA-Exo-induced ICD in cancer cells, adequate exposure to tumor antigens and Hiltonol in situ activates type 1 conventional DCs (cDC1s) and cross-prime tumor-reactive CD8+ T-cell responses, resulting in the development of immunogenicity in poorly immunogenic triple-negative breast cancer.
Efficient tumor suppression in mouse xenograft models of cancer (TNBC) and patient-derived tumor organoids
.
In conclusion, this study found that HELA-Exos exhibited potent antitumor activity in mouse models and human breast cancer organoids by promoting the activation of cDC1 in situ, thereby improving subsequent tumor-reactive CD8+ T cell responses
.
The strategy presented here holds promise for generating in situ DC-primed vaccines and can be extended to various types of cancer
.
As the most potent antigen-presenting cells (APCs), dendritic cells (DCs) are central to the initiation and regulation of innate and adaptive immunity in the tumor microenvironment (TME), with the ability to present tumor-associated antigens (TAAs) on MHC molecules ) and the ability to provide costimulatory/soluble factors to shape antitumor T cell responses
.
Therefore, in numerous clinical trials, a variety of DC-targeted vaccines have been developed to improve cancer immunotherapy
.
Targeted delivery of antigens and adjuvants to DCs in vivo is an important approach to enhance the antitumor effects of DCs
.
Compared to ex vivo generation, in vivo activation and mobilization of DCs allows for vaccine production on a larger scale and allows direct activation of native DC subsets at multiple sites in vivo
.
However, since DC-target receptors, such as DEC205 and DC-SIGN, are not exclusively expressed on tumor-infiltrating DCs, this strategy can also induce antigen-nonspecific activation of the immune system and potential side effects
.
Furthermore, another major challenge in implementing this strategy is the identification of the best immunodominant tumor antigens, such as TAA, TSA and even patient-specific neoantigens
.
Efforts to address these issues are critical to making DC vaccines clinically viable
.
The type of cell death induced in tumor cells affects their efficacy in inducing immunity
.
Immunogenic cell death (ICD) enhances tumor antigen exposure, promotes the release of immunostimulatory tumor cell contents, and facilitates DC uptake of dying tumor cells
.
In this context, ICDs have been approved for whole tumor lysate preparations for autologous DC vaccines
.
Therefore, induction of ICD in tumor cells would be an effective method to maintain adequate exposure of DCs to tumor antigens
.
On the other hand, DCs generally exhibit poor maturity in the TME and are therefore less effective at presenting tumor antigens
.
Adjuvants driving the activation of immunogenic DCs, in particular agonists of TLR3, are being actively studied
.
Administration of TLR3 agonists is highly effective in inducing type 1 conventional DC (cDC1) maturation, which is necessary for the induction of cellular immunity and has been associated with increased survival in patients with certain cancer types due to their efficient processing and crossover
.
Therefore, targeted delivery of ICD inducers and TLR3 agonists into tumor cells would be an ideal approach to activate tumor-infiltrating DCs in situ and avoid interactions in the immune milieu of other sites
.
In recent years, exosomes have attracted attention as drug delivery vehicles because of their low cytotoxicity, ability to maximize drug bioavailability, and excellent target homing specificity
.
The therapeutic potential of exosomes is demonstrated in their growing number of clinical trials for the treatment of chronic kidney disease, non-small cell lung cancer, colon cancer, type 1 diabetes and severe COVID-19
.
Notably, in a mouse model, the chemotherapeutic drug doxorubicin (Dox) was more stable when loaded in breast cancer-derived exosomes and accumulated in tumors more effectively than free Dox for therapy breast cancer
.
Therefore, tumor-derived exosomes (Texs) can be used as cell-free therapeutic vehicles to infiltrate the TME for in situ DC activation
.
Here, we developed and optimized a target-specific exosome formulation loaded with Hiltonol, a TLR3 agonist, and the ICD inducer, human neutrophil elastase (ELANE), to form a target-specific exosome formulation for breast cancer therapy.
In situ DC vaccine
.
Alpha-lactalbumin (α-LA), a breast-specific immunodominant protein expressed in most human breast cancers, is further enriched on the surface of exosomes as a specific tumor-homing protein to enhance Targeting ability and immunogenicity
.
In mouse models and patient-derived tumor organoids, these Hiltonol-ELANE-α-LA engineered exosomes (HELA-Exos) have a robust ability to accumulate in cancer cells after systemic administration, and are compatible with free Hiltonol has better therapeutic effect
.
Therefore, the combination of cell-free exosome-based TLR3 agonists with ICD inducers provides a powerful and novel therapeutic platform for designing DC vaccines for breast cancer
.
Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-022-01515-x
