Cross-talk between microbiota and immune fitness to steer and control response to anti PD-1/PDL-1 treatment

Abstract

Immune Checkpoint Inhibitors (ICIs) are improving the survival of cancer patients, however only the 20-30% of treated patients present clinical benefits. Toxicity represents the major cause of reduced dosage, delayed drug administration and therapy discontinuation. Hence in the context of multiple treatment possibilities, the identification of predictive markers of response and toxicity is a challenging approach for drug selection in order to obtain the best clinical benefit while minimizing the side effects. The loss of the protective function of intestinal barriers that interacts with the environment measured as increased intestinal permeability and the changes occurring in the microbiota composition have been proposed as a mechanism potentially explaining the pathogenesis of immune related toxicity.In this review we discuss the new perspectives on the involvement of PD-1 and PDL-1 in the cross talk between gut microbiota and immune fitness and how gut microbiota impacts on the efficacy of anti-PD-1 and anti-PDL-1 treatments in cancer.

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…464 Additionally, ICIs have been found to influence the gut microbiome composition in patients; dynamic alterations in the gut microbiomes of patients undergoing anti-PD-1 immunotherapy during different treatment cycles have been reported. 465 These studies also elucidate the underlying mechanisms of the observed protection conferred by a favorable gut microbiome. Bacteroides fragilis can enhance the therapeutic response to anti-CTLA-4 mAb in melanoma via the IL-12-dependent Th1 immune response in the lymph nodes and facilitate the maturation and proliferation of intratumoral DCs.…”

AllergoOncology: Microbiota in allergy and cancer—A European Academy for Allergy and Clinical Immunology position paper

“…Moreover, high abundance of Faecalibacterium and low abundance of Bacteroidales were associated with good prognosis and longer progression‐free survival after checkpoint inhibitor treatment . Moreover, toxicity‐related side effects and a dysfunctional intestinal epithelial barrier seem to be attenuated by a beneficial microbiota composition, potentially acting not only via modulation of the host immune response but also via modulation of cancer metabolism …”

A Tool for the Treatment of Gastrointestinal Tumors: Micro- Ecological Immunotherapy

“…PD-1 contains an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosinestimulated motif (ITSM). When PD-1 recognizes its ligand, this interaction induces the phosphorylation of tyrosine residues in the ITSM, leads to the recruitment of tyrosine phosphatase SHP2, induces Zap70 dephosphorylation and inactivation in T cells, and down-regulates TCR signaling [67]. Therefore, PD-1 down-regulates the activity of T cells and inhibits the normal immune response.…”