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Studies have concluded that the number of tumor neoantigens, the degree of T cell infiltration, and the strength of innate sensing are all closely related to the effect of immunotherapy [3,4].
However, as a direct target of immunotherapy, how to increase the number and function of T cells in tumors is still an urgent scientific problem
to be solved.
Cytokines such as IL-2, IL-7, and IL-15 can not only effectively expand T cells, but also play an important role
in the activation and differentiation of T cells.
Therefore, cytokines have always been one of
the hot spots of tumor immunotherapy.
Although high-dose IL-2 has been used in the treatment of renal cell carcinoma, the side effects caused by treatment remain a major factor limiting the widespread use of this therapy [5].
At the same time, whether cytokines can overcome resistance to immune checkpoint blockade therapy has not been demonstrated
.
Mesenchymal stem cells (MSCs) are commonly used to treat chronic inflammation and tissue damage
.
Recent research results in Professor Fu Yangxin's laboratory show that MSCs can also reshape the immune microenvironment and activate anti-tumor immune responses by delivering immune molecules without causing significant side effects [6].
It suggests that MSCs can be used as novel cell therapies to target solid tumors
.
On December 6, 2022, Professor Fu Yangxin's team from Tsinghua University School of Medicine published a title in the journal Nature Cell Biology IL-2 delivery by engineered mesenchymal stem cells reinvigorates CD8+ T cells to overcome immunotherapy resistance in cancer
.
The study found that the endogenous cytokine IL-2 plays a crucial role
in maintaining the number and function of CD8 T cells in tumors.
After blocking the IL-2 signaling pathway, the effect of immune checkpoint blocking therapy completely disappeared
.
By modifying mesenchymal stem cells, the authors achieved controllable IL-2 delivery to targeted tumors, effectively controlled tumors in a variety of mouse tumor models, and was able to break anti-PD-L1 drug resistance
.
At the same time, the cell therapy did not produce significant side effects
.
Further mechanistic studies have shown that SIL2-EMSC treatment relies on pre-existing CD8 T cells within tumors, especially amplified PD1+TIM3- subsets
.
Finally, SIL2-EMSC therapy can not only effectively improve the effect of chemotherapy and immunotherapy, but also show good anti-tumor effect in humanized mouse models, which provides a new idea
for the development of a new generation of immunotherapy strategies.
The research team first compared gene expression
of CD8 T cells in early (10 days) and late (20 days) tumors through single-cell sequencing.
The results showed that T cells within advanced tumors had a highly depleted phenotype, accompanied by weakened IL-2 signaling
.
Further experiments showed that the cell subsets of PD1+TIM3- in advanced tumors, especially stem cell-like depleted CD8T cells (TSLE: Tcf1+PD1+TIM3-TOX+CD44+CD8+ The proportion of PD1+TIM3+ cells, especially terminally depleted CD8 T cells (Tte: Tcf1-PD1+TIM3+TOX+CD44+CD8 +) The proportion has increased
significantly.
At the same time, the protein level of IL-2 and the phosphorylation level of STAT5 were also significantly reduced
.
It was proved that IL-2 played an important role
in maintaining the function of T cells and controlling tumor growth.
When the IL-2 receptor was blocked, the number of CD8 T cells was significantly reduced, and the therapeutic effect of anti-PD-L1 disappeared completely
.
In summary, IL-2 plays a crucial role
in anti-tumor immune response, especially in immune checkpoint blockade therapy.
The previous research results of our group showed that super IL-2 mutants (SIL2, decreased affinity with α receptors, increased affinity with β receptors) can produce better therapeutic effects than wild-type IL-2 [7].
However, there is still a certain percentage of recurrence of tumors after treatment
.
At the same time, the protein injected in the tumor will still enter the peripheral circulation and cause side effects
.
In order to solve the above problems, IL-2 delivery
targeting tumor tissue is realized.
The research team used the tumor tropism of MSCs [8,9] to further modify them and obtain the following characteristics: 1.
Expression of quinone oxidoreductase (NQO1) to enhance viability in the tumor microenvironment; 2.
Introduce hypoxic reaction elements (HRE) to achieve SIL2 secretion
specific in a hypoxic environment.
In vivo experiments have shown that SIL2-EMSC can survive tumor tissues for 8 days and control tumors
in various tumor models such as MC38, B16, CT26 and 4T1.
More importantly, in advanced tumors, SIL2-EMSC is able to produce synergistic anti-tumor effects with ICBs and avoid treatment-induced side effects
.
Mechanistic studies have shown that SIL2-EMSC treatment relies on intratumor-infiltrating CD8 T cells
.
After treatment, the proportion of PD1+TIM3- stem-cell-like T cells in CXCR5+ increased, while the proportion of PD1+TIM3+ terminal depleted T cells in CD39+ decreased
.
PD1+TIM3- expresses higher IL2β receptors and has lower apoptosis
compared to PD1+TIM3+ cells.
Under the action of SIL2-EMSC, it becomes the main cell subpopulation in tumor tissue, and achieves tumor killing
by secreting IFNγ.
After SIL2-EMSC treatment, mice not only produced antigen-specific T cell responses and memory T cells, but were also able to control
metastatic tumors and distant tumors through tumor drainage lymph nodes.
Finally, the authors conduct a preliminary exploration
of the clinical translational potential of SIL2-EMSC therapy.
In humanized mouse models, SIL2-EMSC was also able to exhibit good antitumor activity, promote TCF1-positive CD8 T cell differentiation, and produce synergistic therapeutic effects
with ICB therapy.
As one of the most important evaluation indicators of cell therapy, the authors also evaluated
the safety of SIL2-EMSC therapy.
SIL2-EMSC is not only cleared by the host's immune system, but because EMSC expresses NQO1, EMSC clearance
can also be achieved using the NQO1-targeting chemotherapy drug β-lapachone.
Moreover β DNA damage caused by lapachone can cause innate sensing in the host [10], further enhancing the adaptive immune response against
。
In summary, this study demonstrates the important role
of cytokine IL-2 in influencing the fate of intratumor T cells in immunotherapy.
Developed novel therapeutic strategies
that use mesenchymal stem cells to target tumor tissues for cytokine delivery.
It provides new ideas
for cell therapy and tumor targeted delivery.
The corresponding author of the study is Professor Yangxin Fu of Tsinghua University School of Medicine and Assistant Professor
Jian Qiao of the University of Texas Southwestern Medical Center.
Dr.
Joonbeom Bae, Dr.
Longchao Liu and Dr.
Casey Moore are co-first authors
of the paper.
Original link:
https://doi.
org/10.
1038/s41556-022-01024-5
Dr.
Longchao Liu is about to return to China to set up a laboratory to study immunotherapy and T cell function, if you are interested in job positions and project collaboration, please contact liulongchao1988@live.
com
.
Platemaker: Eleven
References
1.
Topalian, S.
L.
et al.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
N Engl J Med366, 2443-2454 (2012).
2.
Postow, M.
A.
, Callahan, M.
K.
& Wolchok, J.
D.
Immune Checkpoint Blockade in Cancer Therapy.
J Clin Oncol 33, 1974-1982 (2015).
3.
Rizvi, N.
A.
et al.
Cancer immunology.
Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
Science 348, 124-128 (2015).
4.
Lu, C.
et al.
DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity.
Cancer Cell 39, 96-108 e106 (2021).
5.
Rosenberg, S.
A.
IL-2: the first effective immunotherapy for human cancer.
J Immunol 192, 5451-5458 (2014).
6.
Moore, C.
et al.
Exogenous signaling repairs defective T cell signaling inside the tumor microenvironment for better immunity.
JCI Insight 7 (2022).
7.
Sun, Z.
et al.
A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8(+) T-cell response and effective tumor control.
Nat Commun 10, 3874 (2019).
8.
Kidd, S.
et al.
Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging.
Stem Cells 27, 2614-2623 (2009).
9.
Chulpanova, D.
S.
et al.
Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment.
Front Pharmacol 9, 259 (2018).
10.
Li, X.
et al.
NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance.
Nat Commun 10, 3251 (2019) (scrollable up and down).
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