Army Medical University, Sun Yat-sen University and Nanjing University Cell published: New strategies to enhance anti-tumor immunotherapy

Blocking PD-1/PD-L1 signaling can alter cancer treatment and is thought to release failed tumor-reactive CD8+ T cells
in the tumor microenvironment (TME).
However, recent studies have also suggested that systemic tumor-reactive CD8+ T cells may respond to
PD-1/PD-L1 immunotherapy.
These differences highlight the importance of
further determining the tumor-specific CD8+ T cell response to PD-1/PD-L1 blockade.

On October 7, 2022, Lilin Ye, Xu Lifan, Sun Bicheng of Nanjing University and Zhonghui Tang of Sun Yat-sen University jointly published a joint communication entitled "The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in" online at Cell Draining lymph nodes," which used multiple preclinical tumor models and found that a subset of tumor-specific CD8+ T cells in tumor-draining lymph nodes (TdLNs) had no failure but exhibited typical memory features
.

TdLNs-derived tumor-specific memory (TTSM) cells establish memory-related epigenetic programs
early in tumorigenesis.
More importantly, after adoptive metastasis, TdLN-TTSM cells exhibit excellent anti-tumor therapeutic effects and are considered true responders to
PD-1/PD-L1 blockers.
Together, these findings highlight the usefulness of TdLN-TTSM cells to enhance anti-tumor immunotherapy
.

In addition, on October 5, 2022, Michael Karin of the University of California, San Diego and Sun Beicheng of Nanjing University jointly published a research paper entitled "Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome" online in Nature, which found that matrix metalloproteinase cleavage of Col I (cCol I) and intact Col I (iCol I) have opposite effects
on PDAC bioenergy, macropinocytosis, tumor growth and metastasis.
cCol I activates the discoid protein domain receptor 1 (DDR1)-NF-κB-p62-NRF2 signaling pathway to promote PDAC growth, while iCol I triggers DDR1 degradation and inhibits PDAC growth
.
Compared with patients with high levels of cCol I, DDR1 and NRF2 in tumors, median survival was improved
in patients with iCol I enrichment and low expression of DDR1 and NRF2 in tumors.
NF-κB or mitochondrial organisms that inhibit ddr1-stimulated occur to prevent tumors from occurring in wild-type mice, but not
in mice expressing MMP-resistant ColI.
In conclusion, the study found that the different effects of tumor matrix on PDAC growth and metastasis, as well as on patient survival, are mediated through the Col I–DDR1–NF-κB–NRF2 mitochondrial biogenesis pathway, whose targeted components can provide therapeutic opportunities
.

Typical features of memory CD8+ T cells formed by acute viral infection include antigen-independent self-renewal, intense proliferative bursts, and rapid transformation into effector CD8+ T cells
when antigens meet again.
However, chronic viral infections or cancers often drive failing CD8+ T cells to differentiate, causing them to lose their memory differentiation potential and exhibit hierarchical deficits
.
At the same time, depleted CD8+ T cells upregulate a range of co-inhibitory receptors, such as PD-1, Tim-3, and TIGIT, and establish a unique epigenetic program that produces irreversible epigenetic "scars" at gene loci associated with failure, such as Tox and Pdcd1
.

Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway mediated durable remission in a group of cancer patients, and these effects are often attributed to reversal
of CD8+ T cell failure in the tumor microenvironment (TME).
However, not all depleted CD8+ T cells respond to PD-1/PD-L1
ICBs.
Depleted CD8+ T cells in TME are highly heterogeneous, including at least a subset
of progenitor cells of depleted T (TPEX) cells and end-failing CD8+ T (TEX) cells.

Although some studies suggest that TPEX cells expressing transcription factor (TF) TCFf-1 in TME may be the primary responders to PD-1/PD-L1 ICBs, a growing body of evidence has also highlighted the potential role
of systemic CD8+ T cells in the PD-1/PD-L1 ICB response.

Draining lymph nodes (dLNs) regulate systemic CD8+ T cell responses, which are related to
the efficacy of PD-1/PD-L1 ICBs in tumors.
However, in tumor dLNs (TdLNs), the differentiation status of tumor-reactive CD8+ T cells and their potential response to ICBs remain unclear
.

Using multiple preclinical tumor models, the study found that a subset of tumor-specific CD8+ T cells in tumor-draining lymph nodes (TdLNs) did not fail, but exhibited typical memory features
.

TdLNs-derived tumor-specific memory (TTSM) cells establish memory-related epigenetic programs
early in tumorigenesis.
More importantly, after adoptive metastasis, TdLN-TTSM cells exhibit excellent anti-tumor therapeutic effects and are considered true responders to
PD-1/PD-L1 blockers.
Together, these findings highlight the usefulness of TdLN-TTSM cells to enhance anti-tumor immunotherapy
.