Engineered probiotics linked to T cells improve colorectal tumor control in mice

Engineered probiotic bacteria physically attached to therapeutic T cells improved tumor localization, coordinated local immune signaling and produced stronger control of colorectal tumors in mouse models, according to a peer-reviewed experimental study in Science Bulletin. A team led by scientists at Nanjing Drum Tower Hospital created a hybrid system called T-FOLactis by joining engineered Lactococcus lactis to the surface of T cells through bio-orthogonal “click chemistry.” In the reported mouse experiments, tumor burden fell by 78.1% relative to saline-treated controls and by 65.0% relative to conventional adoptive T-cell therapy, while median survival increased from 22 days to 46 days. The investigators did not observe overt systemic toxicity under the tested conditions, but the findings remain preclinical and do not establish a clinical benefit in people.

Adoptive T-cell therapy has produced remarkable responses in some blood cancers, but transferred T cells can have difficulty reaching solid tumors, remaining active after arrival and functioning in the immunosuppressive environment around cancer cells. The researchers addressed several of these challenges by equipping T cells with an engineered bacterium rather than simply administering the two components together. Their FOLactis strain produces a fusion protein containing Flt3L and OX40L, two immune-regulatory signals designed to support dendritic-cell activation and T-cell responses. Modified molecules on the bacterial and T-cell surfaces reacted selectively under physiological conditions, creating a stable probiotic–T-cell chimera. T-FOLactis accumulated more effectively within tumors than either conventional T cells or T cells administered alongside unattached FOLactis. The engineered bacteria were also recovered mainly from tumor-associated tissues, with only minimal detection in major organs or blood.

The physical linkage changed the cellular and signaling environment inside tumors. Dendritic cells, which help coordinate T-cell activation, showed greater activation and were positioned closer to CD8-positive T cells. This arrangement placed antigen presentation, cell adhesion, co-stimulation and T-cell activity within the same local setting. Interleukin-18, or IL-18, was one component of the response: blocking IL-18 reduced several important CD8-positive T-cell functions and weakened the antitumor effect of T-FOLactis. IL-18 alone, however, could not explain the stronger activity. Unattached FOLactis induced substantial IL-18 production but did not reproduce the antitumor performance of the physically linked system. These results suggest that the location of immune stimulation, as well as its measured production, may be important to the platform’s performance. Single-cell sequencing supported this interpretation by showing strengthened communication between dendritic cells and CD8-positive T cells, including molecular interactions involved in antigen presentation, cell adhesion and co-stimulation. Some of these effects were partially reduced when IL-18 was blocked.

The researchers also tested the platform with primary human T cells. Human T-FOLactis showed stronger activation-associated features, increased interferon-gamma production and improved killing of human cancer cells in vitro, indicating that key functional properties could be reproduced in a human cellular system. The work nevertheless remains at an experimental stage: most of the current evidence comes from mouse colorectal cancer models, and additional studies in humanized systems, patient-derived models and more clinically representative tumor models will be needed. Future clinical development would also require standardized manufacturing and quality-control procedures for bacterial loading, stability, sterility and biological potency. The study therefore demonstrates a preclinical engineering strategy in which functional biological components can be attached to therapeutic T-cell surfaces, organizing immune-stimulating activity directly around the cells as they enter tumors. Whether this approach can provide safe and effective treatment in patients remains to be established.

Subject of Research: Preclinical probiotic-linked T-cell therapy in mouse colorectal cancer models

Article Title: Can probiotics help T cells fight solid tumors more effectively?

Article References: Can probiotics help T cells fight solid tumors more effectively?. Original publication (Bibliographic details unavailable.)

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Keywords: engineered probiotics, T-cell therapy, colorectal cancer, bacterial immunotherapy, click chemistry, IL-18, dendritic cells, tumor localization, mouse models, probiotics, help, cells