Hedgehog blockade remodels the gut microbiota and the intestinal effector CD8+ T cells in a mouse model of mammary carcinoma.

Given the gut microbiome's rise as a potential frontier in cancer pathogenesis and therapy, leveraging microbial analyses in the study of breast tumor progression and treatment could unveil novel interactions between commensal bacteria and disease outcomes. In breast cancer, the Hedgehog (Hh) signaling pathway is a potential target for treatment due to its aberrant activation leading to poorer prognoses and drug resistance. There are limited studies that have investigated the influences of orally administered cancer therapeutics, such as Vismodegib (a pharmacological, clinically used Hh inhibitor) on the gut microbiota. Using a 4T1 mammary carcinoma mouse model and 16 S rRNA sequencing, we longitudinally mapped alterations in immunomodulating gut microbes during mammary tumor development. Next, we identified changes in the abundance of commensal microbiota in response to Vismodegib treatment of 4T1 mammary tumor-bearing mice. In addition to remodeling gut microbiota, Vismodegib treatment elicited an increase in proliferative CD8+ T cells in the colonic immune network, without any remarkable gastrointestinal-associated side effects. To our knowledge, this is the first study to assess longitudinal changes in the gut microbiome during mammary tumor development and progression. Our study also pioneers an investigation of the dynamic effects of an orally delivered Hh inhibitor on the gut microbiome and the gut-associated immune-regulatory adaptive effector CD8+ T cells. These findings inform future comprehensive studies on the consortium of altered microbes that can impact potential systemic immunomodulatory roles of Vismodegib.

Informing the new developments and future of cancer immunotherapy : Future of cancer immunotherapy.

The application of cancer immunotherapy (CIT) in reinforcing anti-tumor immunity in response to carcinogenesis and metastasis has shown promising advances, along with new therapeutic challenges, in the landscape of cancer care. To promote tumor growth and metastasis, cancer cells aim to manipulate their microenvironment by mediating a crosstalk with various immune cells through the secretion of chemokines, cytokines, and other associated factors. Understanding this crosstalk is the key to discovering the best targets for improved immunotherapies and clinical strategies in cancer treatment. Here, we review the tumor immune crosstalk in cancer growth and metastasis. This review also highlights the development and expansion of CIT over the years. Moreover, we highlight clinical challenges and limitations involving immune-related adverse events, treating cancer patients with pre-existing autoimmune diseases, and the management of immunotherapy-induced treatment resistance. Possible clinical solutions to these current challenges in CIT are also proposed. Altogether, this review can contribute to the formation of pre-clinical and treatment-related strategies that further develop the availability and effectiveness of CIT.

Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer.

The tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression. Here, we discovered a functional role for Hedgehog (Hh) signaling in promoting Treg differentiation and immunosuppressive activity, and when Hh activity was inhibited, Tregs adopted a Th17-like phenotype complemented by an enhanced inflammatory profile. Mechanistically, Hh signaling promoted O-GlcNAc modifications of critical Treg and Th17 transcription factors, Foxp3 and STAT3, respectively, that orchestrated this transition. Blocking Hh reprogramed Tregs metabolically, dampened their immunosuppressive activity, and supported their transdifferentiation into inflammatory Th17 cells that enhanced the recruitment of cytotoxic CD8+ T cells into tumors. Our results demonstrate a previously unknown role for Hh signaling in the regulation of Treg differentiation and activity and the switch between Tregs and Th17 cells in the tumor microenvironment.