Single-cell transcriptome and TCR profiling revealed the immunosuppression caused by Macrophages and T cells in the chemoresistant oral tongue squamous cell carcinoma

Abstract

Abstract Background After surgical treatment, chemotherapy is one of the most common strategies for advanced oral squamous cell carcinoma (OSCC). The majority of patients, especially those with advanced OSCC of the tongue, are refractory to chemotherapy or have acquired resistance, and the underlying mechanism remains unknown. Methods The transcriptomes of 62,375 single cells from 15 samples (14 primary OTSCC (PT, n = 13), recurrent OTSCC (RT, n = 1), and normal tongue tissue (NT, n = 1) were analyzed. The recurrent OTSCC tissue was obtained from the patient who has received a combination of chemotherapeutic drugs for the past four years since the initial surgery in 2018. Additionally, TCR sequencing was undertaken on three samples (RT, PT, and NT; n = 1 each). The composition, purpose, and lineage relationship of macrophage and T lymphocytes within three different groups were then determined using an integrative analysis. Results We observed a greater infiltration of immune cells in recurrent OTSCC than in primary OTSCC, as indicated by the accumulation of dysfunctional cytotoxic CD8 + T cells and macrophages. As indicated by the distinct distribution and functions of C1Qs + and SPP1 + tumor-associated macrophages, respectively, macrophages in PT exhibited pro-tumor and anti-inflammatory effects, whereas macrophages in RT showed greater non-polarization. In addition, we identified a substantial population of CD8 + T cells in RT patients that exhibited a continuous transition from regulatory to cytotoxic T cells. In addition, we identified two clusters of substantially increased cytotoxic CD8 + T cells and regulatory CD4 + T cells in RT patients. The interaction between macrophages and T cells was evaluated lastly. We found that SPP1 and MIF may be responsible for immunosuppression in the microenvironment of OTSCC tumors following long-term chemotherapy. Conclusion Long-term chemotherapy induced distinct OTSCC tumor microenvironment transcriptomes, particularly immunosuppression in recurrent tumors, which may correlate with tumor chemoresistance.