In a recent preview article published in the Cell Host & Microbe Journal, researchers discussed the work by Chen et al., published in April 2023 in the journal Science, which describes the use of engineered commensal bacteria to increase antitumor immunity by improving tumor antigen cross-presentation to T cells.

Study: Cracking cancer with engineered skin commensals. Image Credit: KaterynaKon/Shutterstock.com

Background

An area of cancer research that has been progressing rapidly in recent times is the engineering of bacteria to improve the immunity generated against tumor antigens.

However, hitherto, the research has largely focused on using Escherichia coli to complement the metabolic requirements of the immune cells and boost their responses in the tumor microenvironment.

The skin microbiome contains bacteria that are generally commensal and do not trigger immune responses or result in inflammation.

However, some bacteria, such as Staphylococcus epidermidis can trigger adaptive immune responses that are highly specific but have no known function. The authors discuss the study by Chen et al., which uses engineered S. epidermidis bacteria to present tumor antigens and boost antitumor immune responses.

About the study

In the study by Chen et al., the researchers engineered S. epidermidis bacteria to express tumor antigens specific for melanomas in an attempt to evaluate the use of these engineered bacteria as adjuvant therapy for skin cancers.

The S. epidermidis bacteria were modified to express variants of the ovalbumin or OVA antigen, which could stimulate the transgenic OVA-specific αβ-T cell receptors expressing CD4⁺ (OT-II) and CD8⁺ (OT-I) T cells.

The restriction systems of S. epidermidis, a Gram-positive bacterium, were bypassed, and the transformation efficiency was increased using a hyperosmolar sorbitol solution.

Furthermore, three different strains with various protein presentation systems were used to address the interference by the undomesticated bacteria in presenting non-native antigens.

One of the strains presented the full-length ovalbumin protein in the cytoplasm. In contrast, the other strains presented ovalbumin on its peptides on the cell wall through covalent binding using an S. aureus wall-spanning region.

The twin-arginine translocation pathway secretion proteins were combined with the antigen constructs to generate the secreted versions of the tumor antigens.

Additionally, the team of researchers also tested the OT-I and OT-II T cell responses against these secreted antigens, first through in vitro experiments and then in vivo using mice models.

Results

The results reported topical applications of the S. epidermidis strains that coded for the full-length ovalbumin, the OT-II peptide. This peptide stimulates the CD4⁺ T cells, or the OT-I peptide stimulates the CD8⁺ T cells, able to reduce melanoma tumors in mice models. The high infiltration of CD8⁺ T cells also indicated that the antitumor response was mediated by ovalbumin.

Furthermore, the antitumor immune response triggered by the topical application of these strains was also found to induce systemic immune responses, which was evidenced by the targeting and reduction of the lung lesions induced by the intravenous injection of malignant cells in mice models and the involvement of both CD4⁺ T cells and CD8⁺ T cells.

Additionally, the absence of systemic or local inflammation indicated that using S. epidermidis did not cause adverse reactions.

When the researchers used heat-killed strains to test the therapeutic benefits of the process, no immune responses were observed, indicating that the persistence and viability of the commensal skin bacteria in the tumor environment and the continued expression of the antigens were essential for the antitumor immune responses to be stimulated.

The utility of this method in the treatment of other cancers was also demonstrated by Chen et al. when they used the topical application of engineered strains of commensal skin bacteria in treating prostate cancer using mice models.

Additionally, a vaccination approach using the same engineered commensal bacteria prevented the establishment and growth of injected tumor cells. The immune responses induced by the engineered bacteria were also found to have similar mechanisms of action with immune-checkpoint blockade therapy.

Conclusions

To conclude, the article discussed the study by a team of researchers led by Michael Fischbach of Stanford University in which engineered strains of commensal skin bacterium S. epidermidis were used to express tumor antigens such as complete ovalbumin or its peptides to induce antitumor immune responses.

Overall, the results indicated that the topical application of these engineered bacteria elicited systemic immune responses that reduced melanoma tumors in mice models.

The translatability of the method was also demonstrated using prostate cancer mice models. S. epidermidis bacteria was also safe and elicited no inflammation or adverse reactions.

Source:

• Chen , E. Y., Bousbaine, D., Veinbachs, A., Atabakhsh, K., Dimas, A., Yu, V. K., Zhao, A., Enright, N. J., Nagashima, K., Belkaid, Y., & Fischbach, M. A. (2023). Engineered skin bacteria induce antitumor T cell responses against melanoma. Science, 380(6641), 203–210. doi: 10.1126/science.abp9563. https://www.science.org/doi/10.1126/science.abp9563

Journal reference:

• Galiè, S. and Nezi, L. (2023) "Cracking cancer with engineered skin commensals", Cell Host & Microbe, 31(6), pp. 919-920. doi: 10.1016/j.chom.2023.05.023. https://www.sciencedirect.com/science/article/abs/pii/S1931312823002160