Targeting tumoral Lactobacillus iners to improve outcomes in cervical cancers

Cervical cancer remains the second most common cancer killer of women worldwide, with an annual incidence of more than 600,000 and an annual death rate of 300,000. Further, cervical cancer disproportionately affects communities of medically underserved and minority women within the US and abroad, and improved therapies are urgently needed. Primary and secondary prevention approaches are also variably effective – even prior to the COVID-19 pandemic, just 1 in 8 girls was vaccinated against human papillomavirus (HPV), the cause of 90% of cervical cancers. Vaccination rates also dropped sharply during the pandemic, even in the United States. Current World Health Organization (WHO) estimates of HPV vaccine uptake rates is 21%. The vast majority of cervical cancers that are diagnosed after primary and secondary prevention fail are locally advanced cervical cancer (LACC). Approximately 40% of women diagnosed with LACC will relapse and die of disease even with standard-of-care curative treatment, cisplatin-based chemoradiotherapy (CRT). CRT has remained the standard-of-care for more than two decades, and novel approaches have failed to improve outcomes. We have identified a critical prognostic factor, a bacteria called Lactobacillus iners (L. iners), in the cervical tumor microbiome, which rewires tumor metabolism to utilize lactate and is associated with treatment resistance and poor survival. Further, commensal Lactobacilli (lactic acid bacteria) in other tumor sites often driven by lactate, such as head and neck and lung cancers, also appear to lead to treatment resistance and poor survival. Our objective is to understand specifically how L. iners and other lactic acid bacteria influence cancer cell and immune cell metabolism using state-of-the-art proximity proteomics and mass cytometry (Aim 1). We will also test novel therapeutic approaches to target either tumor resident bacteria by eliminating or replacing specific bacterial species (Aim 2), or metabolic effects of tumor resident bacteria via local bacterial engineering or systemic metabolism targeting anti-cancer therapies (Aim 3). Targeting cervical tumor bacteria as a therapeutic (“Bugs as Drugs”) is a paradigm-shifting idea, capitalizing on the relative simplicity of the cervicovaginal microbiome and its tendency to be dominated by Lactobacillus species, and not only will this study lead to improved microbiome- based therapeutics to improve outcomes in cervical cancer, but this proof-of-concept model could be used to inform tumor microbiome-based therapeutics across cancer types.