Gut metabolomics profiling of non-small cell lung cancer (NSCLC) patients under immunotherapy treatment

Abstract

Background: Despite the efficacy of immune checkpoint inhibitors (ICIs) only the 20-30% of treated patients present long term benefits. The metabolic changes occurring in the gut microbiota metabolome are herein proposed as a factor potentially influencing the response to immunotherapy. Methods: The metabolomic profiling of gut microbiota was characterized in 11 patients affected by non-small cell lung cancer (NSCLC) treated with nivolumab in second-line treatment with anti-PD-1 nivolumab. The metabolomics analyses were performed by GC-MS/SPME and 1 H-NMR in order to detect volatile and non-volatile metabolites. Metabolomic data were processed by statistical profiling and chemometric analyses. Results: Four out of 11 patients (36%) presented early progression, while the remaining 7 out of 11 (64%) presented disease progression after 12 months. 2-Pentanone (ketone) and tridecane (alkane) were significantly associated with early progression, and on the contrary short chain fatty acids (SCFAs) (i.e., propionate, butyrate), lysine and nicotinic acid were significantly associated with long-term beneficial effects. Conclusions: Our preliminary data suggest a significant role of gut microbiota metabolic pathways in affecting response to immunotherapy. The metabolic approach could be a promising strategy to contribute to the personalized management of cancer patients by the identification of microbiota-linked "indicators" of early progressor and long responder patients.

The Agnostic Role of Site of Metastasis in Predicting Outcomes in Cancer Patients Treated with Immunotherapy

“…In the context of novel biomarkers, indoleamine 2,3-dioxygenase (IDO) [ 32 , 33 ], the enzymes family involved in tryptophan catabolism, CD73, an immunosuppressive ecto-enzyme involved in the production of adenosine [ 34 , 35 , 36 , 37 , 38 ], and microbiome [ 39 , 40 , 41 ] seem to have a promising role. The complete and comprehensive immune profile requires simultaneous and dynamic evaluation of many biomarkers that cooperate for the success or failure of the immune response, rather than research on a single biomarker.…”

Microbiome-derived metabolome as a potential predictor of response to cancer immunotherapy

“…Investigators found that patients with early disease progression (defined as disease progression within 3 months of starting nivolumab) had a microbiome metabolome that was characterized by low levels of both SCFA (propionic, butyric, acetic and valeric acids) and amino acids (lysine, isoleucine and glutamic) but high levels of alkanes, methyl-ketones and p-cresol. 8 In contrast to this, a recently published study of (n=85) metastatic melanoma patients receiving anti-CTLA-4 therapy confirmed that low baseline butyrate and low baseline propionate (serum) were associated with increased progression free survival (p=0.0015 and p=0.0029, respectively). 9 As these patients were receiving single agent treatment, further studies are required to investigate the effects of SCFA on treatment outcomes in patients receiving combination immunotherapy.…”

“…Investigators found that patients with early disease progression (defined as disease progression within 3 months of starting nivolumab) had a microbiome metabolome that was characterized by low levels of both SCFA (propionic, butyric, acetic and valeric acids) and amino acids (lysine, isoleucine and glutamic) but high levels of alkanes, methyl-ketones and p -cresol. 8 …”

Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer

“…The presence of SCFAs (propionic, butyric, acetic and valeric acids) regulates the intestinal microenvironment by reducing pH and impacting the microbial function and composition [ 66 ]. Besides various gut disorders, gut microbiota also play an important role in central nervous system disorders, the immune system and cancer malignancies [ 67 ]. Although the role of butyrate in fueling tumor cells proliferation has been described [ 68 ], SCFAs have been generally perceived as tumor suppressors because they induce cancer cell differentiation and apoptosis [ 69 ].…”