Recent studies have indicated that therapeutic antibodies targeting PD-L1 show remarkable efficacy in clinical trials in multiple tumors and that a melanoma cell-intrinsic PD-1: PD-L1 axis promotes tumor growth.,However, few studies have shown tumor-intrinsic PD-L1 effects in malignant melanoma initiating cells (MMICs).,Here, we aim to determine the possible regulatory effects of PD-L1 on MMICs.,The ALDEFLUOR kit was used to identify ALDH+ MMICs.,Flow cytometry was used to examine the expression of PD-L1 on ALDH+ MMICs.,To determine the role of PD-L1 in MMICs self-renewal, we cultured melanoma cells with anti-PD-L1 and measured tumorsphere formation and apoptosis.,In addition, the effects of anti-PD-L1 on tumorigenicity and residual ALDH+ MMICs in tumors were evaluated in vivo.,We demonstrated that melanoma cell-intrinsic PD-L1 was expressed in ALDH+ MMICs.,Blocking PD-L1 in melanoma cell lines impaired tumorsphere formation and induced the apoptosis of sphere cells.,In addition, blocking PD-L1 inhibited tumor growth in vivo.,We observed residual ALDH+ MMICs within the tumor.,The results showed that blocking PD-L1 also significantly decreased the residual ALDH+ MMICs in the tumors.,In conclusion, these results suggest a new mechanism underlying melanoma progression and PD-L1-targeted therapy, which is distinct from the immunomodulatory actions of PD-L1.
The composition of the intestinal microbiota influences the development of inflammatory disorders.,However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition.,Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis.,Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development.,We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis.,Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis.,Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy.,A subset of cancer patients treated with immune checkpoint blockade develops colitis.,Here the authors show that lower abundance of Bacteroidetes and vitamin B biosynthetic modules in fecal samples of melanoma patients can predict their susceptibility to colitis following anti-CTLA-4 treatment.