Advanced cancer treatment was dominated by chemotherapy and radiotherapy, the progress in target therapy and immunotherapy has greatly improved the outcome of cancer patients, especially the administration of ICIs benefits many of them. However, part patients treated with ICIs still failed to achieve significant efficacy and prolonged PFS. Although there are reported that the expression level of PD-L1, tumor mutation burden, infiltrate lymphocytes could partly predict the efficacy of ICIs treatment[20–22], finding out more precise predictive factor is essential to improve the immunotherapy.
The microbiota is a relatively fragile but extremely important ecosystem influencing host immunity. The microbiota loses homeostasis in a constitutive manner is closely related to tumor progression, raising the question of whether antibiotics changing the composition of microbiota affects immunologic processes, especially its immunotherapy. In recent years, there has been an upsurge of interest in gut microbiota due to its regulatory potential for the immunotherapy of cancers. It was first evaluated in murine models and preclinical studies showed the contribution of gut microbiome in the efficacy of ICIs. Civan et al. demonstrated that tumor progression of melanoma in mice harboring distinct Bifidobacterium was nearly abolished with anti-PD-L1 combination treatment. Augmented dendritic cell function leading to enhanced CD8 + T cells priming and accumulation in the tumor microenvironment mediated the effect. Similarly, tumor growth of sarcomas in mice housed in specific pathogen-free condition was inhibited by anti-CTLA-4 in contrast to mice housed in germ-free condition, and the activation of splenic lymphocytes and tumor-infiltrating lymphocytes mediated by anti-CTLA-4 could be significantly decreased in germ-free and antibiotic-treated mice. In addition, the higher alpha diversity and relative abundance of Ruminococcaceae bacteria in melanoma patients was confirmed to be associated with enhancing systemic and anti-tumor immunity.The important role of microbiota in tumors makes them interesting forecast indicators for the immunotherapy.
Antibiotics are recognized to be able to shift the microbiota composition, decrease the microbiota diversity and impact on taxonomic richness, which returns to its baseline within 1–3 months or even longer after antibiotics discontinuation[25, 26]. Moreover, according to the statistics in 2010, the estimated global consumption of antibiotics was 70 billion individual doses, and the annual rates continue to grow steadily. Given this widespread use of antibiotics, their potential effects on gut microbiota-associated immunotherapy and links with prognostic outcomes has substantial implications for public health. In the present study, our analyses of large and independent cohorts of patients with advanced cancer treated with contemporary ICIs showed that antibiotics administration was associated with both reduced PFS and OS in patients receiving ICIs treatment. In addition, the data indicated that the difference between patients with and without antibiotics use in PFS was more significant than OS, although a moderate heterogeneity was presented in PFS (I2 = 53%; P = 0.02). Regarding the differences in inclusion criteria of various researches, such as tumor types, statistical methods, broader intervention time of antibiotic medication[11, 13], and polycentric source, the heterogeneity for PFS was reasonable.
Our study has some limitations that should be considered when interpreting the results. As inherent in other meta analyses of observational studies, we could not exclude the possibility that some residual factors may confound the association between antibiotics and immunotherapy efficacy, such as the categories, doses, and duration of antibiotics, because we did not have access to individual patient data of the included cohorts. Also, factors such as age at onset of treatment, or gender may potentially affect the association between antibiotics and immunotherapy efficacy, these factors were generally not reported in the original studies, so they could not be analyzed accordingly in the meta-analysis. In addition, we did not include studies in other databases, not written in English, or published as a conference abstract. However, including literature reports from PubMed, EMBASE, Web of Science, and the Cochrane Library published only in English should have covered the majority of the cases. Finally, the main tumor types were focused on lung and urinary system included in the meta-analysis, more types and larger sample size are needed to determine the association between antibiotics and immunotherapy efficacy.