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INTERNATIONAL CONGRESS OF

CancerGenetics

• Impact of Host Genome and Microbiome on Cancer Immunotherapy Response

• mozhdeh Mahmoudabadi,¹ Fatemeh Sarveghadmoghadam,^2,*
  1. B.Sc. in Microbiology Islamic Azad University of Mashhad
  2. B.Sc. in Biotechnology Islamic Azad University of Mashhad
  
  
  
• Introduction: A fundamental question in cancer immunotherapy is why patients with similar clinical conditions exhibit markedly different responses. For instance, a melanoma patient may experience significant improvement with PD-1 inhibitors, while another patient undergoing the same protocol remains resistant. Previous studies have shown that the gut microbiome plays a crucial role in enhancing or suppressing anti-tumor immune responses. However, to fully understand these differences, it is essential to also consider the host genome and the tumor-associated microbiome, as these layers collectively influence patients’ responses to immunotherapy.
• Methods: Differences in patients’ responses to immunotherapy are primarily driven by a complex interplay between the host genome, the gut microbiome, and the tumor microbiome. Genetic variants in antigen presentation genes and immune pathways can alter immune cell sensitivity to the tumor and shape the tumor microenvironment either in favor of or against immune responses. Strain-level metagenomic sequencing has revealed that the gut microbiome can either stimulate or suppress immune responses. Tumor-resident microbiota, through direct interactions with immune cells and modulation of the local microenvironment, simultaneously affect treatment efficacy. For patients unresponsive to immune checkpoint inhibitors (ICIs), experimental interventions have demonstrated that targeted microbiome modulation can improve therapeutic outcomes. In this context, fecal microbiota transplantation (FMT) from responder patients to non-responders has led to a partial restoration of responsiveness to ICIs. Additionally, probiotics such as Lactobacillus and Bifidobacterium, along with high-fiber diets, enhanced gut microbiome diversity and stability, strengthened immune responses, and improved the efficacy of immunotherapy. These findings provide strong evidence that targeted microbiome modulation can serve as a practical and scientifically grounded approach to personalized cancer treatment.
• Results: Host genome: Genetic variants in HLA genes and antigen presentation pathways alter immune cell recognition of tumors. Efficient alleles enhance tumor peptide presentation and increase PD-1 inhibitor response. Variations in the IFN-γ pathway can modulate MHC-I expression and CD8+ T cell infiltration, while polymorphisms in TGF-β and immune-suppressive pathways can create an immunosuppressive microenvironment, explaining treatment resistance. Gut microbiome: Bacteria such as Akkermansia muciniphila and Bifidobacterium longum produce metabolites like propionate and butyrate, which modulate dendritic cell and Treg activity, enhancing immune responses. Strains of Faecalibacterium prausnitzii adjust cytokine levels (increasing IFN-γ and reducing IL-10), fostering an environment conducive to CD8+ T cell activity. Conversely, strains of Bacteroides fragilis and Fusobacterium can generate an immunosuppressive environment via TLR4 activation and IL-10/TGF-β signaling. Strain-level differences can explain why patients with similar bacterial species exhibit variable responses. Tumor microbiome: Tumor-resident bacteria such as Fusobacterium nucleatum can inhibit TIGIT receptors on NK and T cells via Fap2 protein, facilitating immune evasion. In contrast, bacteria like Streptococcus and Corynebacterium enhance dendritic cell infiltration and antigen presentation. Tumor microbiota can also metabolize drugs or alter the tumor chemical environment (e.g., ROS levels), indirectly affecting treatment efficacy.
• Conclusion: Evidence suggests that the combination of a patient’s genetic and microbial profiles increases the likelihood of successful cancer treatment. The microbiome not only modulates responses to immunotherapy but can also activate or deactivate chemotherapeutic drugs, influencing resistance and toxicity. Microbiome-targeted interventions, including dietary modifications, probiotic/prebiotic supplementation, and FMT, can personalize and improve therapy. However, challenges such as inter-individual microbiome variability, dual effects of microbial metabolites, and standardization of FMT remain and warrant further research.
• Keywords: Cancer immunotherapy, Gut microbiome, Tumor microbiome, Host genome, Fecal microbiota transplantatio