Tumor microbial burden drives immune responses through regulation of Interferon signaling
Haoyue Liu, Jeong-Hoon Jang, Fuduan Peng, Hajar Rajaei, Vidhi Chandra, Le Li, Dhwani N. Rupani, Sedigheh Taghinezhadsaroukalaei, Yuehui Zhao, Erika Y. Faraoni, Thais F. Bartelli, Olivereen Le Roux, Virginia Tahan, Fernando Jimenez-Arancon, Seyda Baydogan, Amir Hossein Mohseni, Javier A. Gomez, Mitesh Patel, Jared K. Burks, Barbara Miño Galvez, Daniel E. Carvajal-Hausdorf, Erika Ruiz-García, Edith A. Fernandez-Figueroa, Scott Kopetz, Steven B. Maron, Andrea Cercek, Erick M. Riquelme, Nicholas E. Navin, James Robert. White, Linghua Wang, Luis A. Diaz, Florencia McAllisterAbstract
Tumor microbes are increasingly recognized for modulating tumor behavior and therapy responses. Intratumoral microbial burden (ITMB) analysis across cancers revealed regulation of immune pathways, and activated mast cells, mostly in colorectal (CRC) and gastric (STAD) cancers. High ITMB CRC leads to interferon regulation and is associated with improved outcomes in advanced disease. Single-cell sequencing revealed induction of interferon-related genes (IRGs) within microbes-containing human CRC. GI-luminal mismatch repair deficiency (MMRd) tumors had higher ITMB than proficient tumors (MMRp). In a rectal MMRd cohort with 100% remission after immune checkpoint blockade (ICB), tumor microbes and microbes-containing mast cells increased. In ICB-sensitive syngeneic murine MMRd tumor models, local tumor microbial depletion, impaired ICB efficacy while downregulating IFN signaling. Forced upregulation of IRGs in ADAR1-deficient cancer cells restored immunotherapy responses during microbial ablation. These data highlight dynamic interplay between ITMB, host defense, and immunogenicity which seems key to determine therapy responses