16S V3-V4 reads from mouse fecal samples Raw sequence reads. Mus musculus

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. However, how interactions between the host and the microbiota influence the ability of the immune system to restrain tumor growth is poorly understood. Here, we show that altered intestinal microbiota flora and enhanced Toll-like receptors (TLRs), dendritic cells (DCs) and T-cell dependent anti-tumor immunity, limit tumor expansion. These changes seen in mice lacking the RING finger protein 5 (RNF5) ubiquitin ligase, which exhibit attenuated activation of the unfolded protein response (UPR) components, including spliced X-box-binding protein-1 (sXBP1) and activating transcription factor 4 (ATF4). Reduced expression of UPR in intestinal epithelial cells coincided with increased expression of inflammasome components, recruitment and activation of DC and reduced expression of antimicrobial peptides. Reduced UPR expression was also seen in murine and human melanoma specimens that responded to immune checkpoint therapy. Co-housing of Rnf5–/– and WT mice largely abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, that were enriched in Rnf5-/- mice establishes anti-tumor immunity and restricted melanoma growth in germ-free WT mice. Collectively, our data suggest that altered UPR signaling, exemplified in Rnf5-/- mice, causes changes in gut microbiota composition and anti-tumor immunity to control melanoma growth.

越来越多的研究证据表明，肠道微生物组(gut microbiome)在抗肿瘤免疫中发挥关键作用。然而，宿主与微生物群之间的相互作用如何影响免疫系统抑制肿瘤生长的能力，目前仍未被充分阐明。本研究发现，肠道菌群紊乱以及Toll样受体(TLRs)、树突状细胞(DCs)与T细胞依赖的抗肿瘤免疫增强，可抑制肿瘤增殖。上述表型可见于环指蛋白5(RNF5)泛素连接酶缺陷小鼠，该类小鼠的未折叠蛋白反应(UPR)相关组分激活受损，包括剪接型X盒结合蛋白1(sXBP1)与激活转录因子4(ATF4)。肠上皮细胞中未折叠蛋白反应表达下调，同时伴随炎性体组分表达上调、树突状细胞招募与激活增强，以及抗菌肽表达降低。在对免疫检查点治疗产生应答的小鼠及人黑色素瘤标本中，同样观察到未折叠蛋白反应表达下调的现象。将Rnf5基因敲除(Rnf5–/–)小鼠与野生型(WT)小鼠共同饲养后，其抗肿瘤免疫与肿瘤抑制表型基本消失；而将Rnf5基因敲除小鼠体内富集的11株细菌（包括B. rodentium）移植给无菌野生型小鼠，则可使其获得抗肿瘤免疫并抑制黑色素瘤生长。综上，本研究结果提示，以Rnf5基因敲除小鼠为代表的未折叠蛋白通路信号异常，可通过改变肠道菌群组成与重塑抗肿瘤免疫，进而调控黑色素瘤的生长。