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Oral probiotics can enhance the effects of immunotherapy
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Oral probiotics can enhance the effects of immunotherapy.
Oral probiotics can enter tumors outside the digestive tract, enhance T cell function, and enhance the effect of immunotherapy.
The application of immune checkpoint inhibitor (ICI) therapy to restore anti-tumor immunity is a core component of current cancer treatment and has shown unprecedented efficacy in some cancer patients.
For example, blocking programmed cell death-1 (PD-1) or its ligand PD-L1 unleashes the antitumor response of T cells and has shown strong clinical efficacy, but only 40% of melanoma patients respond to treatment generate a response.
Therefore, methods that can further enhance the anti-tumor ability are needed to improve the efficacy of ICI.
Previous studies have shown that endogenous factors, such as tumor antigen presentation, tumor mutational burden, and exogenous factors, including microbiome composition and probiotic consumption, can modulate the efficacy of ICIs, leading to increased interest in the use of probiotics to enhance health in cancer patients .
Recently, a research team led by Professor Marlies Meisel from the University of Pittsburgh in the United States published a paper entitled “Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment (Roy’s intratumor Dietary tryptophan metabolites released by Lactobacillus facilitate immune checkpoint inhibitor therapy)”.
To test whether some of the most commonly used probiotics affect tumor growth in preclinical melanoma. To provide evidence for the potential role of probiotics in promoting ICI efficacy and survival in patients with advanced melanoma.
The results showed that in mice fed a tryptophan-rich diet, the commensal bacterium Lactobacillus reuteri migrated to melanoma tumors located outside the digestive tract and released the metabolite indole-3-aldehyde (I3A) to act on T cells Enhance the immune response and improve the therapeutic effect of immune checkpoint inhibitors.
Lactobacillus reuteri induces antiumor immunity and promotes ICI in preclinical melanoma
The researchers used a preclinical melanoma model (C57BL/6 mice) to test the antitumor activity of four commonly used probiotics: Bifidobacterium longum (Bl), Lactobacillus reuteri (Lr), Lactobacillus johnsonii ( Lj) and Escherichia coli (Ec).
Figure 1. Tumor growth curve and mouse survival curve of B16-F0 tumor-bearing mice orally administered with different probiotics
In contrast, daily oral administration of Bl, Ec, or Lr from 1 day after cell implantation effectively suppressed melanoma in C57BL/6 wild-type mice transplanted with B16-F0 tumors compared with control (PBS) growth (Figure 1A and 1B), and improved survival (Figure 1C). Among them, Lr has the most significant antitumor effect.
Therefore, the researchers hypothesized that the underlying mechanisms of different probiotics to promote tumor suppression are different, and explored the mechanism by which Lr, the intestinal commensal probiotic with the strongest tumor suppressive ability in this animal model, inhibited the growth of melanoma.
The investigators found that at all time points assessed (9 days early, 11 days mid, and 17 days late), Lr tilted the tumor microenvironment (TME) toward an antitumor, immunostimulatory environment characterized by the production of interferon -Expansion of CD4-Th1 and CD8-Tc1 cells.
Figure 2. Significant improvement in tumor control in mice treated with Lr combined with αPD-L1
Single-cell RNA-sequencing analysis of TME-derived CD8 T cells identified 13 distinct CD8 T cell clusters and found that Lr treatment resulted in upregulation of the suppressive T cell receptors Tigit, Pdcd1, and Lag3 in tumor-infiltrating CD8 T cells. expression increased significantly.
Tumor control was significantly improved in mice treated with Lr combined with αPD-L1 (Fig. 2).
Intratumoral live Lr mediates antumor effects
There is increasing evidence for the presence of tumor microbiota in tumors of the distal gut, and viable bacteria have been recovered from breast and pancreatic tumors in patients.
The investigators’ observations confirmed that intragastric administration of exogenous Lr can drive translocation, which can metastasize to distal intestinal melanoma.
This translocation is independent of established microbiome, tumor formation, and gut barrier dysfunction, does not compromise gut barrier integrity, and instead translocates via vascular and lymphatic pathways to include liver, spleen, and mesenteric lymph nodes systematic organization.
Tryptophan catabolite I3A released by Lr promotes antitumor immunity
To explore the mechanism by which Lr drives tumor suppression, the research team further investigated whether Lr-mediated tumor suppression is specific to melanoma models.
Figure 3. Antitumor effects of Lr in different tumor models
We detected viable Lr in YUMM1.7 melanoma, MC38 colon adenocarcinoma, and MMTV-PyMT breast cancer tumors, respectively, and observed significant tumor growth inhibition (Fig. 3A-3C). This suggests that translocation of Lr to distal gut tumors is not limited to B16 melanoma.
Among the immunomodulatory metabolites released by Lr, the indole derivative I3A was shown to play a key role in Lr-induced Tc1 cell-mediated antitumor immunity.
Figure 4. Inhibitory effect of oral administration of Lr ΔArAT and Lr wild type
The ability to catabolize dietary tryptophan (Trp) to I3A was eliminated by genetically modifying the Lr strain (lacking the aromatic amino acid aminotransferase class I/II gene – Lr ΔArAT).
Strikingly, the tumor suppressive effect of oral administration of Lr ΔArAT was in stark contrast to that of Lr wild type (Fig. 4A-4C).
Although both strains were isolated from tumors at similar levels, genetically modified LrΔArAT failed to inhibit tumor growth, improve survival, or elicit potent antitumor Tc1 immunity.
This proves that the secretion of I3A by Lr is a key link in promoting anti-tumor immunity.
After establishing I3A’s role in Lr-mediated tumor suppression, the team also assessed whether oral administration of I3A alone was sufficient to induce an antitumor response. The results showed that oral administration of I3A inhibited tumor growth and increased survival in a dose-dependent manner.
Figure 5. Tumor inhibitory effect of I3A and/or PD-L1 treatment in B16-F0 tumor-bearing mice
Compared with single-agent PD-L1, I3A combined with PD-L1 treatment significantly inhibited tumor growth and significantly decreased tumor weight relative to the control group.
These data suggest that Lr-derived I3A is both necessary and sufficient to promote antitumor Tc1 immunity, suppress melanoma, and further enhance ICI.
I3A mediates antitumor immunity by activating the aryl hydrocarbon receptor (AhR) in C8 T cells
Marlies Meisel et al. found that I3A released by Lr directly acts on AhR in CD8 T cells to promote Tc1 function.
Figure 6. Lr-derived I3A induces antitumor immunity in Tc1 cells in an AhR-dependent manner in vivo
To test the requirement for AhR activation in Lr-mediated antitumor immunity in vivo, the researchers constructed an AhR-specific deletion mouse model (Ahr fif CD8 Cre+).
Both Lr- and I3A-mediated tumor suppression and survival benefit were abolished in Ahr fif CD8 Cre+ mice (Fig. 6A–5D), suggesting that Lr-mediated tumor suppression through I3A release is dependent on CD8 T cell-intrinsic AhR activation .
These results suggest that Lr-derived I3A promotes Tc1 differentiation and effector function in a CD8 T cell-intrinsic, AhR-dependent manner.
Dietary fortified ICI rich in tryptophan
Considering that Lr cleaves dietary tryptophan to the AhR ligand I3A, we assessed whether dietary tryptophan levels affect Lr-mediated antitumor responses.
To this end, mice were placed on tryptophan-rich or deficient diets 4 weeks before tumor cell implantation and were maintained on the respective diets throughout the experiment.
Figure 7. Dietary tryptophan and tumor inhibitory effect
The results showed that a diet low in tryptophan (0.19%) did not fully enhance the ability of Lr to suppress tumor growth, mice receiving a diet high in tryptophan (1.19%) showed Significant tumor suppression and increased survival were observed (Fig. 7A-7C).
In addition, the research team also found that a diet rich in tryptophan independently significantly enhanced the efficacy of PD-L1.
In summary, tryptophan-rich diet can enhance the tumor suppressive effect of Lr; tryptophan-rich diet alone can inhibit tumor growth and enhance ICI.
Evidence for the role of I3A in promoting ICI response and survial in patients with advanced melanoma
To directly investigate the potential role of I3A in influencing the efficacy of ICIs in human melanoma, the researchers measured baseline serum I3A levels in patients with advanced stage IV melanoma (n = 42) using targeted mass spectrometry.
Based on RECIST v1.1 criteria, these patients responded (n = 19) or did not respond (n = 23) to combined IFN-α and αPD-1 immunotherapy.
Figure 8. I3A abundance and ICI efficacy in melanoma patients
Notably, the abundance of exogenous I3A was significantly higher in the serum of ICI responder patients compared with non-responders (Fig. 8A).
By stratifying patients according to high (>70th percentile) and low (<30th percentile) serum I3A levels, it was further found that patients with low I3A levels had systemically high I3A at baseline Patients with significantly prolonged progression-free survival (PFS) and overall survival (Figure 8B-8C).
Taken together, the microbial AhR ligand I3A plays a potential role in promoting ICI response in melanoma patients, contributing to prolonged PFS and overall survival.
Our findings elucidate key microbe-host interactions in the TME that drive spontaneous antitumor immunity and enhance the efficacy of ICI in preclinical melanoma.
More specifically, Lr translocates, colonizes, and persists within tumors and promotes antitumor Tc1 immunity locally through its released AhR agonist and dietary tryptophan catabolite I3A.
Lr-derived I3A directly acts on the CD8 T cell-specific AhR signaling pathway to promote IFN-γ production, where I3A is both sufficient and necessary to enhance ICI.
Furthermore, this study found that a tryptophan-rich diet was sufficient to enhance the efficacy of ICI therapy and that the antitumor effect of a tryptophan-rich diet required AhR activity in CD8 T cells.
In conclusion, this study reveals a potential role of I3A in improving ICI response and prolonging survival in patients with advanced melanoma.
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