On October 13, 2022, Liu Yong's team at Xiangya Hospital of Central South University and Zhang Nu team of the University of Texas published a research paper entitled "TGF-β-dependent lymphoid tissue residence of stem-like T cells limits response to tumor vaccine" on Nature Commun

This article is original from Translational Medicine Network. Please indicate the source when reprinting

Author: Mia

Introduction: TGF-β signal is a necessary signal for CD8⁺T cells to differentiate into tissue-resident memory T cells (T_RM). Although higher frequency of CD8⁺T_RM cells in the tumor microenvironment are associated with better prognosis, blocking TGF-β usually improves prognosis rather than worsens.

On October 13, 2022, Liu Yong's team and Zhang Nu team of the University of Texas published a research paper entitled "TGF-β-dependent lymphoid tissue residence of stem-like T cells limits response to tumor vaccine" on Nature Communications. This study revealed the link between T_RM and stem cell-like T cells, which inhibited the migration and effect differentiation of stem cell-like T cells, resulting in a weakened anti-tumor immunity.

https://www.nature.com/articles/s41467-022-33768-x#Sec1

Research background

01

Continuous exposure to antigen (such as tumor antigen) can induce T cell failure and reduce effector function. Depleted CD8⁺T cells are heterogeneous, while the less depleted subset has stem cells -like characteristics. These stem cell-like CD8⁺ T cells express the transcription factor TCF-1 (T cytokine-1) and maintain the CD8⁺ response during chronic antigen exposure. Importantly, these stem cell-like CD8⁺T cells respond to immune checkpoint blockade therapy and are related to the efficacy of tumor vaccines. However, the signals controlling the maintenance, differentiation and migration of these stem cell-like T cells are not fully understood.

transforming growth factor β (TGF-β) is generally considered an immunosuppressive factor. Blocking the TGF-β signaling pathway has been shown to promote tumor control by targeting tumor stromal compartments or CD4⁺T cell-mediated vascular remodeling. In addition, the system blockade of TGF-β in synergistically works with tumor vaccine or PD-1/PD-L1 blockade, promoting the response of CD8⁺T cells in mouse model. Since most studies on TGF-β on CD8⁺T cells do not combine knowledge of stem cell-like T cells, it is crucial to re-study the role of TGF-β on tumor-specific CD8⁺T cells, especially stem cell-like CD8⁺T cells.

tissue resident memory T cells (T_RM) is a unique population of memory T cells that are isolated from blood circulation and maintained in a self-sustaining manner. T_RM was originally found in an acute infection model and has now been identified as an important component of tissue-specific immunity. Surprisingly, recent studies have shown that stem cell-like CD8⁺T cells produced after chronic viral infection have similar properties to T_RM, that is, they are mostly limited to secondary lymph organs (such as spleen and lymph nodes ) and non-circulating.

However, it is still unclear whether similar situations exist in the tumor immune environment. Most previous studies on tumor-specific CD8⁺T cells have focused on tumor-infiltrating lymphocytes (TIL). Although cancer immune cycle models are widely accepted, tumor-specific CD8⁺T cells in lymphoid organs are largely under-attention. As we all know, TGF-β signaling to CD8⁺T cells is crucial for the differentiation and maintenance of T_RM after acute infection. In tumor immunity, T_RM-like signal is usually positively correlated with the ability of TILs to control tumors. TGF-β promotes T_RM, T_RM limits tumor growth, and TGF-β blockade improves tumor control, but how to fully coordinate this information remains a mystery.

study overview

02

This study demonstrates that tumor drainage lymph node TDLNs play a role as a repository of tumor-specific stem cell-like CD8⁺T cells. Using a mouse melanoma model, the researchers found that in tumor drainage lymph nodes (TDLN), but not in the tumor itself, stem cell-like CD8⁺T cells differentiated into T_RMs in a TGF-β and tumor antigen-dependent manner.In the

T cell-specific TGF-β receptor knockout mice, the response of CD8⁺T cells to tumor vaccine was significantly enhanced. After receiving the melanoma-specific epitope vaccine, most tumor-specific CD8⁺T cells remained in a stem cell-like state, but some cells lost the T_RM state and differentiated into CX3CR1+ effector CD8⁺T cells in TDLN, and then migrated into the tumor. The disruption of TGF-β signaling alters the dynamics of these developmental processes, ultimately improving the migration of effector CD8⁺T cells to tumors. The results of the

study also highlight two unique characteristics of TDLNs in tumor immunotherapy : (1) TDLNs serve as a reservoir of host stem cell-like T cells. (2) TDLNs serve as a trap to limit the migration/differentiation of stem cell-like T cells. Similar to the tumor environment, researchers previously demonstrated that TGF-β promotes the retention of dry-like CD8⁺T cells in lymphoid follicles during chronic viral infection. Therefore, TGF-β-dependent lymphoid tissue resident programs are not tumor-specific and may represent a common feature of Tcf-1⁺CD8⁺T cells.

study summary

03

In summary, after tumor vaccine, TDLN stem cell-like T cells transition from TGF-β-dependent TRM differentiation process to the development process of anti-tumor migration effector factors, and targeting TGF-β blockade can promote this transition.

Reference materials:

https://www.nature.com/articles/s41467-022-33768-x#Sec1

Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment plans. If you need health guidance, please go to a regular hospital for treatment.

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