In a mouse model of carcinogen-induced colorectal cancer (CRC), Overacre-Delgoffe et al. found that colonization by an immunogenic bacterium (Hhep) restricted tumor growth and extended mouse survival. Hhep colonization led to lymphangiogenesis, infiltration of CD4+ T cells, B cells, and CD11c+ cells, and formation of tertiary lymphoid structures (TLS). Hhep- specific Tfh cells were detected in TLS following Hhep colonization, and loss of CD4+ T cells (or specifically Tfh) decreased TLS formation, immune infiltration, and tumor control. In TCGA data, a high Tfh signature was associated with improved progression-free survival in patients with CRC.
Contributed by Alex Najibi
ABSTRACT: The composition of the intestinal microbiota is associated with both the development of tumors and the efficacy of anti-tumor immunity. Here, we examined the impact of microbiota-specific T cells in anti-colorectal cancer (CRC) immunity. Introduction of Helicobacter hepaticus (Hhep) in a mouse model of CRC did not alter the microbial landscape but increased tumor infiltration by cytotoxic lymphocytes and inhibited tumor growth. Anti-tumor immunity was independent of CD8(+) T cells but dependent upon CD4(+) T cells, B cells, and natural killer (NK) cells. Hhep colonization induced Hhep-specific T follicular helper (Tfh) cells, increased the number of colon Tfh cells, and supported the maturation of Hhep+ tumor-adjacent tertiary lymphoid structures. Tfh cells were necessary for Hhep-mediated tumor control and immune infiltration, and adoptive transfer of Hhep-specific CD4(+) T cells to Tfh cell-deficient Bcl6(fl/fl)Cd4(Cre) mice restored anti-tumor immunity. Thus, introduction of immunogenic intestinal bacteria can promote Tfh-associated anti-tumor immunity in the colon, suggesting therapeutic approaches for the treatment of CRC.
Author Info: (1) R.K. Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, P
Author Info: (1) R.K. Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA. (2) R.K. Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA. (3) Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA. (4) R.K. Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA. (5) R.K. Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA. (6) R.K. Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA. (7) Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA. (8) Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA. (9) R.K. Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: timothy.hand@chp.edu.
