The search for causes of resistance to pembrolizumab in lung adenocarcinoma with PD-L1 expression — focus on intestinal microbiome

Abstract

Anti-PD-1 or PD-L1 immunotherapy in some patients with non-small cell lung cancer (NSCLC) may not be effective, despite the high percentage of cancer cells with PD-L1 expression (≥ 50%). TMB (tumor mutation burden), smoking status and low intestinal microbiome diversity may be associated with lack of efficacy of immune checkpoints inhibitors treatment in NSCLC patients. The case presented here concerns a non-smoking female patient with lung adenocarcinoma, in whom, despite the high percentage of PD-L1 positive tumor cells (50%), pembrolizumab therapy was ineffective. Next generation sequencing (NGS) was performed using the FOCUS panel allowing the analysis of 52 genes whose damage is associated with various types of solid tumors, including lung cancer. Benign genetic changes clinically irrelevant for patients with non-small cell lung cancer have been observed. In the meantime, profiling of the patient’s intestinal microbiome was performed, due to the fact that the composition of the intestinal microbiome may be a decisive factor in the lack of response to immunotherapy in patients with high PD-L1 expression and no driver mutations. Low diversity of bacteria in the intestines, with a noticeable dysbiosis (dysbacteriosis), was observed. The presence of bacteria Akkermansia, Enterococcaceae, Bifidobacteriaceae or Coriobacteriaceae, especially the presence of Akkermansia mucinifila seems to be a favourable factor of the possibility of obtaining response to immunotherapy and prolongation of progression-free survival (PFS). In the intestinal microbiome of the presented case, no bacteria from the Verrucomicrobia phylum, to which A. mucinifila belongs, were found. In addition, only 0.011% of Enterococcaceae were found. Studies on the intestinal microbiome in cancer patients receiving immunotherapy appear to be necessary to correctly understand the effect of microbiome composition on the effectiveness of this treatment method.