Dietary low-fiber promotes resistance to immune checkpoint inhibitor immunotherapy in the LSL-KrasG12D Lung Cancer Model

Abstract

Abstract Dietary fiber interaction with the gut microbiota impact gut microbiota composition and is likely to play a large role in affecting the efficacy of immune checkpoint inhibitors (ICIs) therapy. Here we show that a diet with low-fiber promoted lung tumor development and reduced tumor-bearing animal long-term survival in both prophylactic early disease and established late disease of murine LSL-KrasG12D lung cancer model, which displays low neoantigen burden and is refractory to anti-PD-1 antibody. In this model, the administration of anti-PD-1 in the presence of IL-17 neutralization resulted in tumor suppression, indicating that limited intrinsic neoantigen alone was not the primary determinant of resistance to ICIs therapy. Interestingly, dietary low-fiber led to reduced anti-tumor effect of anti-PD-1 and anti-IL-17 partially in gut microbiota-dependent manner. Fecal microbiota transplantation from mice fed low-fiber diet also enhanced lung tumor burden. An altered immune response with significantly reduced gut lamina propria RORgt+IL-17A+ Th17 cells, lung Foxp3+Treg cells, enhanced lung Th17 cells, but no alteration of lung gdTCR+ cells were found in mice fed low-fiber diet. Furthermore, a low-fiber diet led to significant changes in metabolites including a high level of serine in the plasma of animals. Mice fed normal chow with drinking water containing serine increased lung tumorigenesis. Our study demonstrates a functional interconnection between dietary fiber and spontaneous lung tumor development. Supported by grant from NIH/NIGMS(P20-GM135004)