Combination Therapy of TGF-β Blockade and Commensal-derived Probiotics Provides Enhanced Antitumor Immune Response and Tumor Suppression

Abstract

Galunisertib (Gal) is a transforming growth factor (TGF-β) blockade which is being investigated as a potential tumor immunotherapy candidate drug in clinical trials. However, primary or acquired resistance is often found in the recruited cancer patients, which limits its clinical application. Tumor immune microenvironment can be regulated by intestinal microbiota, leading to different therapeutic outcomes. It is hypothesized that manipulation of cancer patients' intestinal microbiome in the early stage of therapy may be a promising strategy to improve the therapeutic efficacy of Gal. Methods : 4T1 and H22 subcutaneous tumor bearing mice were used to evaluate the therapeutic effect. Escherichia coli strain Nissle 1917 (EcN), a widely used probiotic bacteria, was orally delivered to the tumor bearing mice daily along with Gal treatment. Antitumor effect of the combination therapy was evaluated by tumor volume, histological staining of tumor tissues. Furthermore, flow cytometry was performed to analyze the alteration of immune microenvironment in tumor bed after treatment. The suppressing effect of the combination therapy on tumor invasiveness and metastasis was evaluated in both mice and zebrafish xenografts models. Fecal sample 16S rRNA gene sequencing was conducted to analyze changes of intestinal microbial diversity. The effect of intestinal microbiota on tumor suppression after receiving EcN was further tested by fecal transplant. Results : The therapeutic outcomes in tumor growth inhibition and metastasis suppression of Gal were significantly potentiated by EcN, resulting from the strengthened antitumor immunity. EcN was able to relieve the immunosuppressive tumor microenvironment, which was evidenced by enhanced tumor-specific effector T cells infiltration and dendritic cells activation. Intestinal microbiota was modulated by EcN, illustrated by a shift of gut microbiome toward certain beneficial bacteria. Conclusion : These results suggested that Gal combined with EcN might be a novel therapeutic approach with great potential of clinical implications for cancer prevention or treatment.

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…Moreover, reliable biomarkers are also necessary for identifying the susceptible and effective population before administering treatment. For example, an increased ratio of CD8+/CD4+ CD3+ T cells and a number of IFN-γ+CD8+ CD3+ T cells can be used to predict enhanced tumour-specific T cell responses in the combination therapy of galunisertib and intestinal microbiota in HCC [ 173 ]. Similarly, an increased number of IFN-γ+CD8+ T cells are also an indicator of the successful combination treatment of bintrafusp alfa and radiotherapy [ 150 ].…”

Targeting gut microbiota for precision medicine: Focusing on the efficacy and toxicity of drugs

“…One typical example is that the preventive administration of the Lactobacillus casei variety rhamnosus mitigated FOLFOX-induced diarrhea and intestinal mucositis in a mouse model of colorectal cancer 188 . Similarly, combined administration of TGF- β blockade and Escherichia coli Nissle 1917, a probiotic strain, significantly improved the antitumor and immune suppression effects of TGF- β blockade in mice 189 . However, the reliability of supplementing prebiotics and probiotics remains to be questioned because of the lack of strong clinical evidence and the negative experimental results.…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…515 Probiotic EcN1917 can improve tumor-specific Teff cell infiltration and DC activation, significantly hampering HCC growth and metastasis. 516 The suppressive effect of Lactobacillus probiotics on mammary cancer progression has been attributed to diminished IL-6 and enhanced IL-10 in serum and mammary gland cells. 429 Short-term administration of L. johnsonii is associated with attenuated systemic leukocyte genotoxicity in a lymphoma mouse model.…”