Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Colorectal cancer

• T follicular helper cell

• Microbiome

Main Findings

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and patients with late-stage CRC often fail to respond to therapy. In recent years, multiple studies have begun to highlight the role of the gut microbiota in improved anti-tumor immunity. However, the exact mechanism by which the microbiome provides a benefit is lacking. In this study, the authors used a carcinogen-induced orthotopic mouse model of CRC to show that a colon-resident bacteria, Helicobacter hepaticus (Hhep), mediated anti-tumor immunity by increasing tumor infiltration of cytotoxic T lymphocytes (CTLs). Furthermore, in the context of CRC, Hhep colonization induced differentiation of CD4+ T cells into Hhep-specific CD4+ T follicular T helper cells (TFH) cells in the lamina propria and drove an increase in TFH-dependent formation of tertiary lymphoid structures (TLS) within and around tumors. The presence of TFH and TLS was associated with better control over CRC and, in this disease model specifically, microbiome-specific TFH were necessary and sufficient to activate anti-CRC immunity.

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Limitations​

• Mice were gavaged twice, instead of once, with Hhep
  Is this bacteria difficult to engraft? Was it present in mice throughout the study?

• Hhep is not commonly found in humans - associated mostly with liver and gallbladder cancers
  CRC-associated bacteria may be more appropriate to study

• The animal model chosen for this study exhibited high baseline inflammation
  IL10-/- models may be used instead

• The authors suggested augmenting future immunotherapies for late-stage CRC using the most immunogenic intestinal bacteria
  Experiments with checkpoint inhibitors were not carried out in this model/study to support this notion
  Limited patient data provided with no statistical tests conducted
  The authors did not offer a way to screen a large number of bacteria for immunogenicity and safety profiles

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​Significance/Novelty

Thus far, the role of microbiome-specific T cells in anti-tumor responses has not been well-described. In this study, the authors used an adherent bacteria that resides primarily in the colon to highlight the important role of bacteria-specific CD4+ T cells in anti-tumor immunity in CRC. The authors further described the exact mechanism by which anti-Hepp T cell responses were shaped by CRC, providing future implications for combination therapies using immunotherapeutic approaches and targeted modification of the gut microbiota by specific immunogenic bacteria.

Credit

Reviewed by Tamar Plitt as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford and Karolinska Institute.