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. 2022 Dec 19;14(24):6250.
doi: 10.3390/cancers14246250.

Attempting to Identify Bacterial Allies in Immunotherapy of NSCLC Patients

Anna Grenda  1 , Ewelina Iwan  2 , Paweł Krawczyk  1 , Małgorzata Frąk  1 , Izabela Chmielewska  1 , Arkadiusz Bomba  2 , Aleksandra Giza  2 , Anna Rolska-Kopińska  1 , Michał Szczyrek  1 , Robert Kieszko  1 , Tomasz Kucharczyk  1 , Bożena Jarosz  3 , Dariusz Wasyl  2 , Janusz Milanowski  1
Affiliations

Attempting to Identify Bacterial Allies in Immunotherapy of NSCLC Patients

Anna Grenda et al. Cancers (Basel). .

Abstract

Introduction: Factors other than PD-L1 (Programmed Death Ligand 1) are being sought as predictors for cancer immuno- or chemoimmunotherapy in ongoing studies and long-term observations. Despite high PD-L1 expression on tumor cells, some patients do not benefit from immunotherapy, while others, without the expression of this molecule, respond to immunotherapy. Attention has been paid to the composition of the gut microbiome as a potential predictive factor for immunotherapy effectiveness. Materials and Methods: Our study enrolled 47 Caucasian patients with stage IIIB or IV non-small cell lung cancer (NSCLC). They were eligible for treatment with first- or second-line immunotherapy or chemoimmunotherapy. We collected stool samples before the administration of immunotherapy. We performed next-generation sequencing (NGS) on DNA isolated from the stool sample and analyzed bacterial V3 and V4 of the 16S rRNA gene. Results: We found that bacteria from the families Barnesiellaceae, Ruminococcaceae, Tannerellaceae, and Clostridiaceae could modulate immunotherapy effectiveness. A high abundance of Bacteroidaaceae, Barnesiellaceae, and Tannerellaceae could extend progression-free survival (PFS). Moreover, the risk of death was significantly higher in patients with a high content of Ruminococcaceae family (HR = 6.3, 95% CI: 2.6 to 15.3, p < 0.0001) and in patients with a low abundance of Clostridia UCG-014 (HR = 3.8, 95% CI: 1.5 to 9.8, p = 0.005) regardless of the immunotherapy line. Conclusions: The Clostridia class in gut microbiota could affect the effectiveness of immunotherapy, as well as the length of survival of NSCLC patients who received this method of treatment.

Keywords: Clostridia; immunotherapy; microbiome; non-small cell lung cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Plot showing the relative frequency of bacterial phylum based on 16S rRNA of 47 stool samples from NSCLC patients treated or not treated with antibiotics; (b) boxplot showing Bacteroidota content depending on antibiotic therapy up to 4 weeks before immunotherapy.
Figure 2
Figure 2
Boxplots showing the content of (a) Bifidobacteriaceae, (b) Clostridia UCG-014, (c) Rikenellaceae depending on the application of antibiotic treatment, and (d) Butiriciococcaceae depending on the line of immunotherapy.
Figure 3
Figure 3
Boxplots showing the content of (a) Butiriciococcaceae depending on the line of immunotherapy; (b) Clostridia UCG-014 depending on immunotherapy toxicity; (c) Prevotellaceae depending on the histopathological diagnosis; (d) Peptostreptococcaceae depending on the histopathological diagnosis in patients who received first-line immunotherapy. All results concern the patients untreated with antibiotics before immunotherapy.
Figure 4
Figure 4
Boxplots showing the content of (a) Barnesiellaceae, (b) Tannerellaceae, (c) Clostridiaceae, and (d) Ruminococcaceae in the group of patients with the disease control (SD + PR) and progression disease (PD) during first-line immunotherapy. All results concern the patients untreated with antibiotics before immunotherapy.
Figure 5
Figure 5
Boxplot showing Verrucomicrobiota content in patients with different responses to immunotherapy.
Figure 6
Figure 6
Differences in the abundance of individual bacteria in patients with PFS shorter and longer than 6 months. Boxplots showing the content of (a) Bacteroidaaceae, (b) Barnesiellaceae, and (c) Tannerellaceae in the group of patients treated with first-line immunotherapy.
Figure 7
Figure 7
Boxplot showing Firmicutes content in patients with PFS above or below 6 months from the start of immunotherapy.
Figure 8
Figure 8
Differences in the abundance of individual bacteria in patients with OS shorter and longer than 12 months. Boxplots showing the content of (a) Enterobacteriaceae regardless of immunotherapy line; (b) Clostridia UCG-014 in first-line immunotherapy group; (c) Ruminococcaceae in first-line immunotherapy group; (d) Enterobacteriaceae in second-line immunotherapy group; (e) Lachnospiracea in second-line immunotherapy group; (f) Bacteroidaceae in first-line immunotherapy group; (g) Christensenellaceae in first-line immunotherapy group. Boxplots (a–e) show groups untreated with antibiotics before immunotherapy, while boxplots (f,g) concern patients treated and untreated with antibiotics.
Figure 9
Figure 9
Analysis of overall survival in patients who received Immunotherapy depending on the content of (a) Ruminococcaceae), (b) Christensenalceae, and (c) Clostridia UCG-014 regardless of immunotherapy line in the group untreated with antibiotics up to 4 weeks before immunotherapy.
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