Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types. 

Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.

Tumor associated macrophage in HPV+ tumors: Between immunosuppression and inflammation.

CD161 characterizes an inflamed subset of cytotoxic T lymphocytes that have high expression of immune checkpoints while retaining high cytotoxic capability. These cells can be reinvigorated by immune checkpoint blockade and are a biomarker for clinical benefit.

https://aacrjournals.org/cancerimmunolres/article-pdf/doi/10.1158/2326-6066.CIR-22-0454/3268028/cir-22-0454.pdf

CD161 Characterizes an Inflamed Subset of Cytotoxic T Lymphocytes Associated with Prolonged Survival in Human Papillomavirus–Driven Oropharyngeal Cancer

Background The effect of chemoradiation on the anti-cancer immune response is being increasingly acknowledged; however, its clinical implications in treatment responses are yet to be fully understood. Human papillomavirus (HPV)-driven malignancies express viral oncogenic proteins which may serve as tumor-specific antigens and represent ideal candidates for monitoring the peripheral T-cell receptor (TCR) changes secondary to chemoradiotherapy (CRT). Methods We performed intra-tumoral and pre- and post-treatment peripheral TCR sequencing in a cohort of patients with locally-advanced HPV16-positive cancers treated with CRT. An in silico computational pipeline was used to cluster TCR repertoire based on epitope-specificity and to predict affinity between these clusters and HPV16-derived epitopes. Results Intra-tumoral repertoire diversity, intra-tumoral and post-treatment peripheral CDR3β similarity clustering were predictive of response. In responders, CRT triggered an increase peripheral TCR clonality and clonal relatedness. Post-treatment expansion of baseline peripheral dominant TCRs was associated with response. Responders showed more baseline clustered structures of TCRs maintained post-treatment and displayed significantly more maintained clustered structures. When applying clustering by TCR-specificity methods, responders displayed a higher proportion of intra-tumoral TCRs predicted to recognise HPV16 peptides. Conclusions Baseline TCR characteristics and changes in the peripheral T-cell clones triggered by CRT are associated with treatment outcome. Maintenance and boosting of pre-existing clonotypes are key elements of an effective anti-cancer immune response driven by CRT, supporting a paradigm in which the immune system plays a central role in the success of CRT in current standard-of-care protocols.

T-cell receptor determinants of response to chemoradiation in locally-advanced HPV16-driven malignancies

This study identifies a novel pathotype of cervical cancer-associated Lactobacillus iners (L. iners) that results in chemoradiation resistance in vitro and is associated with poor patient survival. Cervical cancer affects over half a million women a year around the world. Treatment for women with locally advanced cancer is delivered with definitive chemoradiation (CRT) but is curative for only 60% of patients. There are few validated molecular markers to identify patients who will respond poorly to treatment. Tumor microbiome features are associated with treatment resistance in patients with colon and pancreatic cancers, and thus we investigated their role in the response of cervical cancer to therapy. We identified a strong association between poor clinical response to CRT and tumors dominated by L. iners. Cancer-associated L. iners promoted in vitro resistance of cervical cancer cells and modified the local tumor immunologic microenvironment, while non-cancer-associated L. iners did not. Assembly of genomes from cancer-derived L. iners also demonstrated pathogenic, metabolic, and immune functions not found in healthy patients.

Cancer-associated Lactobacillus iners are genetically distinct and associated with chemoradiation resistance in cervical cancer

Chemoradiation therapy is a common treatment for HPV-related cancer. The authors show that HPV-specific T cells expand in the tumor over the course of treatment, laying the groundwork for understanding radiation-induced immune response among other cancers. Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16+ patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non–HPV-specific T cells did not. In HPV16+ patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.

Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16+ Cancers

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Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16+ Cancers