Genomic and microbial factors affect the prognosis of anti-pd-1 immunotherapy in nasopharyngeal carcinoma

Abstract

Antibodies targeting the programmed cell death protein-1 (PD-1) molecule have been reported to hold promising antitumor activities in patients with nasopharyngeal carcinoma (NPC). However, only a small subset of NPC patients benefits from the anti-PD-1 monotherapy and factors that affect the treatment response need further investigation. This study aimed to examine the impact of multiple genetic and environmental factors on outcome of anti-PD-1 immunotherapy by identifying tumor size, tumor mutation burden (TMB) based on whole exon sequencing, human leukocyte antigen class I (HLA-I) homo-/heterozygosity and supertypes, blood Epstein-Barr virus (EBV) DNA load, T cell proportions, and interferon-γ(IFN-γ) levels in a cohort of 57 NPC patients that received Nivolumab or Camrelizumab treatment. Moreover, we profiled the longitudinal changes in gut microbiota composition using shotgun metagenomics sequencing. We observed that high TMB combined with HLA-I heterozygosity was associated with improved clinical outcomes. In agreement with previous studies, we found that patients with higher plasma EBV DNA load showed worse progression-free survival. We found no evidence for an effect of gut bacterial diversity on the treatment response, but identified a higher abundance of seven specific gut bacteria at baseline of non-responders, including Blautia wexlera and Blautia obeum, as well as four other bacteria belonging to the Clostridiales order, and one Erysipelatoclostridium. Combined, this study provides insight into the influence of several genetic and environmental factors on anti-PD-1 immunotherapy responses in NPC patients.

The Association between Caffeine Intake and the Colonic Mucosa-Associated Gut Microbiota in Humans—A Preliminary Investigation

“…A previous study showed that patients with type 2 diabetes had higher Erysipelotrichaceae levels than patients with normal glucose tolerance [ 41 ]. There is growing evidence showing the adverse roles of Erysipelotrichaceae and Erysipelatoclostridium play in host lipid metabolism [ 42 ], immune response [ 43 ], inflammation [ 44 ], depression [ 45 ], metabolic-associated fatty liver disease [ 46 ], cancer [ 47 ], and response to cancer immune therapy [ 48 , 49 ]. However, in a human-based study, increased physical activity was associated with a higher relative abundance of Erysipelotrichaceae [ 50 ].…”

Development of a prognostic model to identify the metastatic nasopharyngeal carcinoma patients who may benefit from chemotherapy combination PD-1 inhibitor

“…In recent years, tumor mutational burden (TMB) was found to be correlated with clinical responses to anti-PD-1 therapy in most solid tumor ( 23 , 24 ). A recent study by Zhang reported that NPC patients with high TMB displayed improved clinical responses to anti-PD-1 therapy, as measured by PFS ( 25 ). Therefore, these patients were more likely to be highly aggressive and more likely to benefit from immunotherapy.…”

Modulation of gut microbiota: a novel approach to enhancing the effects of immune checkpoint inhibitors

“…22,23 The importance of specific bacterial composition has been supported by several clinical studies investigating the relationship between different gut microbiota characteristics and clinical benefits (Supplemental Table 1). 20–22,24–43 Most of these studies focused on NSCLC, melanoma, and hepatocellular carcinoma, where alpha diversity and some specific gut microbiome constituents have been associated with successful treatment with ICIs, such as Bifidobacterium species, Lactobacillus species, Akkermansia species, Faecalibacterium species, Firmicutes species, and Lachnospiraceae. A favorable gut microbiome improves effector T-cell function in the peripheral and tumor microenvironment (TME).…”