Liu Yong's team at Xiangya Hospital of Central South University and others have discovered a potential mechanism to enhance tumor vaccine response

This article is the original of Translational Medicine Network, please indicate the source of reprinting

Written by Mia

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

On October 13, 2022, Liu Yong's team at Xiangya Hospital of Central South University and Zhang Nu's team at the University of Texas published a research paper entitled "TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine" in Nature Communications
。 The study revealed a link between T_RM and stem cell-like T cells,_{which inhibits} the migration and effector differentiation of stem cell-like T cells, resulting in weakened
anti-tumor immunity.

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Research background

 01 

Continuous exposure to antigens, such as tumor antigens, can induce T cell exhaustion and reduce effector function
.
Depleted CD8⁺ T cells are heterogeneous, while less depleted subsets have stem-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 associated
with the efficacy of oncology vaccines.
However, the signals that control the maintenance, differentiation, and migration of these stem-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, systemic blocking of TGF-β synergistically with oncology vaccines or PD-1/PD-L1 blockade promotes CD8⁺ T cell response
in mouse models.
Since most studies on TGF-β on CD8+ T cells do not have knowledge of binding stem-like T cells, it is critical
to re-examine 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) are a unique population of memory T cells that are separated from blood circulation and maintained
in a self-sustaining manner.
T_RM was originally discovered in acute infection models 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 confined to secondary lymphoid organs (such as the spleen and lymph nodes) and non-circulating
.

However, it remains unclear whether a similar situation
exists in the immune oncology environment.
Most previous studies of tumor-specific CD8⁺ T cells have focused on tumor-infiltrating lymphocytes (TILs
).
Although cancer immune cycle models are widely accepted, tumor-specific CD8⁺ T cells in lymphoid organs have largely underappreciated
.
TGF-β signaling to CD8⁺ T cells is known to be critical
for the differentiation and maintenance of T_RM after acute infection.
In tumor immunity,_TRM-like signaling is generally 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
.

Overview of the study

 02 

This study demonstrated the role
of tumor-draining lymph node TDLNs as a reservoir of tumor specific stem cell-like CD8⁺ T cell residence.
Using a mouse melanoma model, the researchers found that in tumor-draining lymph nodes (TDLN), rather than in the tumor itself, stem-like CD8⁺ T cells differentiated into T_RMs
in a TGF-β and tumor antigen-dependent manner.

In T-cell-specific TGF-β receptor-conditioned knockout mice, CD8⁺ T cells significantly enhanced their response to tumor vaccines

After receiving melanoma-specific epitope vaccine, most tumor-specific CD8+ T cells remained in a stem cell-like state, but some cells lost their T_RM state, differentiated into CX3CR1+ effector CD8⁺ T cells in TDLN, and subsequently migrated into tumors
.
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 also highlight two unique features of TDLNs in tumor immunotherapy: (1) TDLNs serve as reservoirs for host stem cell-like T cells
.
(2) TDLNs as traps
that limit the migration/differentiation of stem cell-like T cell activity.
Similar to the tumor environment, the researchers previously demonstrated that TGF-β promotes the retention
of dry-like CD8⁺ T cells within lymphfollicles during chronic viral infection.
Thus, TGF-β-dependent lymphoid tissue-resident procedures are not tumor-specific and may represent a universal feature of
Tcf-1⁺CD8⁺ T cells.

Summary of the study

 03 

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

Resources:

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

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