Single-cell transcriptome analysis reveals evolving tumour microenvironment induced by immunochemotherapy in nasopharyngeal carcinoma

Background: Combinatory therapeutic strategy containing immunochemotherapy as part of induction therapy components is one of the current trends in the treatment of high-risk metastatic locally advanced nasopharyngeal carcinoma (NPC). However, the mechanism underlying the heterogeneity of response at the single-cell level has not been underexplored.

Methods: 18 bulks and 11 single-cell RNA sequencing from paired before-treatment and on-treatment samples in patients with treatment-naive high-risk metastatic locally advanced NPCs were obtained. Following quality control, a total of 87 191 cells were included in the subsequence bioinformatics analysis.

Results: Immunochemotherapy was associated with on-treatment tumour microenvironment (TME) remodelling, including upregulation of anti-TMEs signatures, downregulation of pro-TMEs signatures, reversing CD8⁺ T exhaustion, and repolarizing proinflammatory TAMs. For the patients achieving a complete response, the cytotoxic activity of CD8⁺ T cells was stimulated and more interferon-gamma was provided, which would be the key for TAMs proinflammatory repolarization and eventually promote the CD8⁺ T cells maturation in turn. Among patients who did not reach complete response, differentiation and hypoxia signatures for endothelial cells were elevated after therapy. These patients exhibited higher levels of immune checkpoint genes in malignant cells at the baseline (before treatment), and decreased tumour antigen presentation activity, which may underlie the resistance mechanism to therapy.

Conclusions: This study pictures a map of TME modulation following immunochemotherapy-based combination induction therapy and provides potential future approaches.

Highlights: Immunochemotherapy remodeled T cell phenotypes. For the patients achieving complete response, more interferon gamma was provided by CD8⁺ T cells after therapy, which would be the key for TAMs pro-inflammatory repolarization and eventually promote the CD8⁺ T cells maturation in turns. Among patients who did not reach complete response, malignant cells exhibited higher level of immune checkpoint genes before therapy, and decreased tumor antigen presentation activity, which may underlie the resistance mechanism to therapy.