PhD Student San Raffaele Scientific Institute Milano, Lombardia, Italy
Introduction: Although asymptomatic smoldering multiple myeloma (SMM) often precedes symptomatic MM, most patients affected by SMM are only offered active observation, which increases their frustration and anxiety. A link between gut microbiota and MM aggressiveness has been proposed. We previously showed that the human commensal Prevotella heparinolytica (P.h.) expands Th17 cells that migrate from the gut to the bone marrow (BM) where they favor the expansion of neoplastic plasma cells. At odds, P. melaninogenica (P.m.) limits Th17 cell expansion, thus restraining MM aggressiveness. Similarly, in SMM patients, higher levels of BM IL-17 predicted accelerated disease. Because the gut microbiota also contributes to the clinical efficacy of immune checkpoint blockade (ICB) and neoplastic plasma cells selectively express PD-L1, we hypothesized that modulation of the gut microbiota by P.m. limits the expansion of Th17 cells in mice affected by asymptomatic MM, thus fully exploiting the therapeutic potential of anti-PD-L1 against MM.
Methods: C57BL/6J mice challenged with MM cells and Vk*MYC mice affected by asymptomatic MM were treated with P.m. and/or anti-PD-L1 and disease progression was monitored by paraprotein quantification in blood. Anemia provided clinical evidence of symptomatic disease. Modification of the gut microbiota composition after the treatment were assessed by16S rRNASeq and shotgun metagenomics. At sacrifice, gut, spleen and BM were analyzed by flow cytometry. To clarify the mechanism of Th17 induction by the gut microbiota, we conducted in vitro assays.
Results: Administration of P.m. to mice challenged with Vk*MYC-derived MM cells increased the therapeutic efficacy of anti-PD-L1 antibodies limiting the expansion of Th17 cells. Translating the approach in the context of SMM-to-MM evolution, treatment with P.m. in transgenic Vk*MYC mice at the phase of asymptomatic (Early)-MM significantly delayed the progression towards symptomatic (Late)-MM. When P.m. was combined with anti-PD-L1 we further delayed the evolution from Early-MM to Late-MM. Mechanistically, P.m. restrained the expansion of gut-born Th17 cells in the BM without dampening the antitumor cytotoxic response elicited by the ICB. Thus, combination of P.m. and anti-PD-L1 resulted in more favorable Th17/T regulatory cell ratio and CD8/Th17 ratio in the BM. P.m. polarized intestinal DCs to produce less Th17-polarizing cytokines compared to P.h., which conversely promoted Th17 expansion. In vitro stimulation of both human and mouse DCs with P.m. or its conditioned medium reduced polarization of naïve T cells to Th17 cells compared to P.h.
Conclusions: Taken together, our data support the development of microbiota-based strategies in combination with ICB to treat full-blown MM and to prevent progression of patients affected by asymptomatic SMM to full-blown disease.
