Temporal molecular remodeling of T cells informs their possible adaptation in 4T1 tumors.
[BACKGROUND] The triple-negative breast cancer (TNBC) microenvironment undergoes progressive reprogramming, transitioning from an early immune-active state to a late immune-suppressed state.
APA
Iftehimul M, Newman RH, et al. (2026). Temporal molecular remodeling of T cells informs their possible adaptation in 4T1 tumors.. Computational and structural biotechnology journal, 31, 169-178. https://doi.org/10.1016/j.csbj.2025.12.022
MLA
Iftehimul M, et al.. "Temporal molecular remodeling of T cells informs their possible adaptation in 4T1 tumors.." Computational and structural biotechnology journal, vol. 31, 2026, pp. 169-178.
PMID
41550137
Abstract
[BACKGROUND] The triple-negative breast cancer (TNBC) microenvironment undergoes progressive reprogramming, transitioning from an early immune-active state to a late immune-suppressed state. While tumor cell plasticity has been extensively studied, the temporal molecular remodeling of T cells remains poorly defined.
[RESULTS] Transcriptional analysis of T cells within 4T1 TNBC tumors, harvested at one-, three-, and six-weeks post-tumor implantation in the mammary fat pads of BALB/c mice, revealed a decline in transcriptomic signatures associated with T cells from 194 at one week to 156 at six weeks, with a significant late-stage loss or reduction of transcripts related to T cell receptors (TCR), natural killer T, and gamma delta T cells. Furthermore, changes in various temporal signature genes specific to T cell cytokines and transcription factors reflected temporal T cell polarization to CD4 type 1 T helper and type 1 CD8 cytotoxic T cell responses at one week, CD8 cytotoxic follicular T cell skewing at three weeks, and interleukin 17/22 producing CD8 T cell transition at six weeks. The antigen-presenting cell (APC) transcripts deteriorated at six weeks, characterized by reduced expression of co-stimulatory and APC genes. Despite an early dominance of M1-like macrophage genes (e.g., ), persistent expression of arginase 1 () and other M2-associated genes indicated a stable tolerogenic niche.
[CONCLUSIONS] The temporally coordinated immune shifts, such as progressive decline in transcripts associated with T cell functions, TCRs, APCs, and sustained macrophage-driven immunosuppression, suggest tumor-driven adaptation toward immune evasion and identify potential windows for stage-specific immunotherapeutic intervention.
[RESULTS] Transcriptional analysis of T cells within 4T1 TNBC tumors, harvested at one-, three-, and six-weeks post-tumor implantation in the mammary fat pads of BALB/c mice, revealed a decline in transcriptomic signatures associated with T cells from 194 at one week to 156 at six weeks, with a significant late-stage loss or reduction of transcripts related to T cell receptors (TCR), natural killer T, and gamma delta T cells. Furthermore, changes in various temporal signature genes specific to T cell cytokines and transcription factors reflected temporal T cell polarization to CD4 type 1 T helper and type 1 CD8 cytotoxic T cell responses at one week, CD8 cytotoxic follicular T cell skewing at three weeks, and interleukin 17/22 producing CD8 T cell transition at six weeks. The antigen-presenting cell (APC) transcripts deteriorated at six weeks, characterized by reduced expression of co-stimulatory and APC genes. Despite an early dominance of M1-like macrophage genes (e.g., ), persistent expression of arginase 1 () and other M2-associated genes indicated a stable tolerogenic niche.
[CONCLUSIONS] The temporally coordinated immune shifts, such as progressive decline in transcripts associated with T cell functions, TCRs, APCs, and sustained macrophage-driven immunosuppression, suggest tumor-driven adaptation toward immune evasion and identify potential windows for stage-specific immunotherapeutic intervention.