Dynamic regulatory networks of T cell trajectory dissect transcriptional control of T cell state transition

Abstract

T cells exhibit heterogeneous functional states, which correlate with responsiveness to immune checkpoint blockade and prognosis of tumor patients. However, the molecular regulatory mechanisms underlying the dynamic process of T cell state transition remain largely unknown. Based on single-cell transcriptome data of T cells in non-small cell lung cancer, we combined cell states and pseudo-times to propose a pipeline to construct dynamic regulatory networks for dissecting the process of T cell dysfunction. Candidate regulators at different stages were revealed in the process of tumor-infiltrating T cell dysfunction. Through comparing dynamic networks across the T cell state transition, we revealed frequent regulatory interaction rewiring and further refined critical regulators mediating each state transition. Several known regulators were identified, including TCF7 , EOMES , ID2 , and TOX . Notably, one of the critical regulators, TSC22D3 , was frequently identified in the state transitions from the intermediate state to the pre-dysfunction and dysfunction state, exerting diverse roles in each state transition by regulatory interaction rewiring. Moreover, higher expression of TSC22D3 was associated with the clinical outcome of tumor patients. Our study embedded transcription factors (TFs) within the temporal dynamic networks, providing a comprehensive view of dynamic regulatory mechanisms controlling the process of T cell state transition.

Single B Cell Gene Co-Expression Networks Implicated in Prognosis, Proliferation, and Therapeutic Responses in Non-Small Cell Lung Cancer Bulk Tumors

“…TSC22D3 was associated with a good prognosis in NSCLC patients [103]. TSC22D3 was frequently present in the T cell state transitions from intermediate to the predysfunction and dysfunction states [103]. Overall, this study conducted a comprehensive analysis of public single-cell RNA sequencing data and identified DE genes in NSCLC PBL and tumor T cells with prognostic and therapeutic importance.…”

“…TSC22D3 was associated with sensitivity to erlotinib and gefitinib (Tables 1 and 2). TSC22D3 was associated with a good prognosis in NSCLC patients [103]. TSC22D3 was frequently present in the T cell state transitions from intermediate to the predysfunction and dysfunction states [103].…”

Comprehensive bioinformatic analysis of the expression and prognostic significance of TSC22D domain family genes in acute myeloid leukemia

“…Tsc22d3 could play an indispensable role in the tumor microenvironment by influencing all immune system cells that infiltrate the tumor microenvironment [25]. In addition, Tsc22d3 could serve as a pivotal regulator of T cell predysfunction [26]. Recent research shows that the proliferation, survival, and drug resistance of AML cells are sustained and modulated by the bone marrow immunosuppressive microenvironment [27].…”

Comprehensive bioinformatic analysis of the expression and prognostic significance of TSC22D domain family genes in acute myeloid leukemia

“…TSC22D3 could play an indispensable role in the tumor microenvironment by in uencing all immune system cells that in ltrate the tumor microenvironment [44]. In addition, TSC22D3 could serve as a pivotal regulator of T cell predysfunction [45]. Recent research shows that the proliferation, survival, and drug resistance of AML cells are sustained and modulated by the bone marrow immunosuppressive microenvironment [46].…”