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Correlation between gut microbiota and their metabolites and the efficacy of chemotherapy combined with immunotherapy for extensive-stage small cell lung cancer

ABSTRACT:

Gut microbiota has been reported to be associated with the host’s immune system and immunotherapy response, as well as immune-related adverse events (irAEs). Additionally, gut microbial metabolites have various immunomodulatory effects. Our study focused on the differences in gut microbiota and their metabolites between long progression-free survival (PFS) and short PFS in patients with small cell lung cancer before and after chemotherapy combined with immunotherapy. The enrolled patients collected in our department were divided into long PFS and short PFS groups according to whether the PFS was ≥6 months, and the stool samples before and after treatment were analyzed using metagenomics and metabolomics. The results showed that Streptococcus (P = 0.00648), Actinomyces (P = 0.0124), and Roseburia (P = 0.0127) differed between the long and short PFS groups. In the analysis of differential metabolites, we found that indirubin-3'-monoxime (AUC 0.611), stearidonic acid (AUC 0.867), leukotriene B4 (AUC 0.844), trans-cinnamic acid (AUC 0.792), and L-tyrosine (AUC 0.751) could be used as potential biomarkers.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13557 | MetaboLights | 2025-12-23

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13557_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13557_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13557_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13557_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:The mammalian gut harbors a diverse microbial community (gut microbiota) that mainly consists of bacteria. Their combined genomes (the microbiome) provide biochemical and metabolic functions that complement host physiology. Maintaining symbiosis seems to be a key requirement for health as dysbiosis is associated with the development of common diseases. Previous studies indicated that the microbiota and the host’s epithelium signal bidirectional inducing transcriptional responses to fine-tune and maintain symbiosis. However, little is known about the host’s responses to the microbiota along the length of the gut as earlier studies of gut microbial ecology mostly used either colonic or fecal samples. This is of importance as not only function and architecture of the gut varies along its length but also microbial distribution and diversity. Few recent studies have begun to investigate microbiota-induced host responses along the length of the gut. However, these reports used whole tissue samples and therefore do not allow drawing conclusions about specificity of the observed responses. Which cells in the intestinal tissue are responsible for the microbially induced response: epithelial, mesenchymal or immune cells? Where are the responding cells located? Furthermore, the gut microbiota has been implicated in epigenetic regulation of the host’s transcriptional profile. We used using extensive microarray analysis of laser capture microdissection (LCM) harvested ileal and colonic tip and crypt fractions from germ-free mice before and during the time course of colonization with a normal microbiota (on days 1, 3, 5 and 7) to investigate the microbiota-induced transcriptional responses and their kinetics in specific and well-defined cell populations of the host’s epithelium. Ileum and colon segments were dissected from germ-free 10-12 weeks old female C57Bl/6 mice and on day 1, 3, 5 and 7 after colonization, washed and frozen as OCT blocks. Cryosections were prepared from these OCT blocks and tip/crypt fractions isolated using laser capture microdissection.

Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.

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Correlation between gut microbiota and their metabolites and the efficacy of chemotherapy combined with immunotherapy for extensive-stage small cell lung cancer

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