Lack of consistent effect of dietary fiber on immune checkpoint blockade efficacy across diverse murine tumor models

Abstract

Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain low in most cancers. Recent research suggest that dietary fiber enhances ICB response in melanoma patients and murine preclinical models through microbiome-dependent mechanisms. Yet, the robustness of this effect across cancer types and dietary contexts remains unclear. Specifically, prior literature compared grain-based chow (high fiber) to low-fiber purified diet, but these diets differ also on other dimensions including phytochemicals. Here we investigated, in mice fed grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin), metabolite levels and ICB activity in multiple tumor models. The blood and fecal metabolome were relatively similar between mice fed high- and low-fiber purified diets, but differed massively between mice fed purified diets or chow, identifying the factor as diet type, independent of fiber. Tumor growth studies in three implantable and two spontaneous genetically engineered tumor models revealed that fiber has a weaker impact on ICB (anti-PD-1) efficacy than previously reported. In some models, dietary modulation impacted ICB activity, but not in a consistent direction across models. In none of the models did we observe the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high-fiber purified diet but low efficacy in low-fiber purified diet. Thus, dietary fiber appears to have limited or inconsistent effect on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie the clinical correlations between fiber consumption and immunotherapy outcomes.