​Nat Immunol Song Erwei/Su Shicheng team reveals new strategies to promote T cells into tumors

Tumor immunotherapy has won the Nobel Prize in Medicine for 18 years and is currently one of the fastest growing cancer treatments
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But currently only about 20-30% of patients benefit, so it is important to find new immunotherapy targets
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The anti-tumor specific immune response can be roughly divided into 7 steps: 1) tumor antigen release; 2) antigen presentation; 3) T cell education and activation in draining lymph nodes; 4) T cell migration to the tumor; 5) T cell penetration Blood vessels enter the tumor; 6) T cells recognize tumor cells; 7) T cells kill tumor cells (Figure 1)
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At present, the targets of tumor immunotherapy are for different steps, such as PD-1/PD-L1 antibody for 7); CTLA-4 antibody for 3); CAR-T for 6); tumor vaccine for 2), etc.
(Figure 1)
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However, the only anti-tumor specific immune response that is not covered by effective drugs is step 4) to promote T cell migration (Figure 1)
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However, it is a very common clinical phenomenon that there are very few anti-tumor T cells in tumor tissues
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A large number of studies have reported that the important reason for the immunosuppression of solid tumors is that there is no or very little T cell infiltration (such as "immune desert")
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Even if there is T cell infiltration, the tumor-promoting Th2 or Tregs are the main ones
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Regarding its underlying mechanism, since the research mainly believes that naive T cells are more induced to differentiate into immunosuppressive T cells (Treg, Th2), cytotoxic T lymphocytes CTL (cytotoxic T lymphocytes) and Th 1 are more likely to be induced to apoptosis, etc.

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In addition, it is unclear whether there are other T cell subsets that regulate tumors.
In particular, whether there is a difference in the ability of anti-cancer/pro-cancer T cell subsets to migrate to tumors is currently lacking reports
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Figure 1 The principle of tumor immunotherapy (picture from Immunity 39(1):1-10, 2013, with question mark added) June 17, 2021, Song Erwei/Su Shicheng's research group from Sun Yat-sen Memorial Hospital of Sun Yat-sen University published online in Nature Immunology A research paper entitled Targeting Regulator of G-protein Signaling 1 in Tumor-specific T cells Enhances Their Trafficking to Breast Cancer found that the ability of anti-tumor CTL and Th1 cells to migrate to tumors is significantly weaker than that of immunosuppressive Th2 and Tregs Cell
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The mechanism is that the transcription of IFN-STAT1 pathway in CTL and Th1 cells up-regulates RGS1 (regulator of G protein signaling), and RGS1 inhibits the ability of CTL and Th1 to migrate to the tumor
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Targeting RGS1 can increase the infiltration of anti-tumor T cells and enhance the effect of immunotherapy
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The study found that in the tumor microenvironment, patients with less infiltration of anti-tumor lymphocytes (Th1 and CTL) and more infiltration of immunosuppressive lymphocytes (Th2) have a significantly poorer prognosis.
One of the reasons for this phenomenon is Th1 and The ability of CTL to migrate to the tumor is significantly weaker than that of Th2 cells, and it does not depend on the expression levels of chemokines and their receptors
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This suggests that the function of the chemokine receptor in T cells is impaired rather than the expression level of the receptor
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The chemokine receptors are mostly G protein-coupled receptors (GPCR).
After the chemokines are combined with GPCRs, the GDP at the Gα subunit nucleotide binding site is converted to GTP, which activates the third Aggregate G protein separates it into Gα and Gβγ, and then regulates intracellular signaling pathways
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The RGS (Regulator of G-protein Signaling) family of proteins belong to GTPase accelerating proteins (GAPs), which accelerate the hydrolysis of GTP on the Gα subunit into GDP and make the downstream pathways enter an inactive state
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It was found that Th1 and CTL highly expressed RGS1 in the peripheral blood of breast cancer patients, and it was negatively correlated with the local invasion of the tumor, and correlated with the patient's poor prognosis
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Further mechanism studies have found that RGS1 inhibits the activation of calcium ion pathways downstream of these GPCRs by binding to the chemokine receptors CXCR3, CXCR4 and CCR4, thereby inhibiting the ERK and AKT signaling pathways and impairing the migration ability of CTL and TH1
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Silencing RGS1 can restore the activation of GPCR downstream pathways and promote the recruitment of CTL and Th1 cells by CXCL9, CXCL10, CXCL11, CXCL12 and other chemokines
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To further explore its mechanism, the research group found that the transcription of RGS1 is regulated by the IFNγ-STAT1 pathway
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Previous studies have reported that in the tumor and its microenvironment, activation of the IFNγ-STAT1 pathway can cause the expression of a large number of chemokines, such as CXCL9, CXCL10, CXCL11, etc.
These chemokines can recruit CTL and Th1 cells to the tumor
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However, in immune cells, activation of the IFNγ-STAT1 pathway will not only amplify the local inflammatory response of the tumor, but also transcribe the expression of many immune checkpoint molecules, such as PD-L1, IDO, etc.
, as a negative feedback method to inhibit T cell activity
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In this study, it was also found that the IFNγ-STAT1 pathway of CTL and TH1 cells was activated, and RGS1 was heavily transcribed, which inhibited the ability of CTL and TH1 cells to migrate to tumors through the circulatory system
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In TH2 cells, STAT1 activity is low, RGS1 transcription is low, and the migration ability of TH2 cells is not affected.
The difference is that breast cancer has less anti-tumor T cell infiltration and more tumor-promoting T cell infiltration.
One of the important reasons for the phenotype (Figure 2)
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Figure 2 Schematic diagram of the mechanism of RGS1 inhibiting the migration of anti-tumor lymphocytes (CTL, Th1) to the tumor.
Further, this study established mouse models of breast cancer and lung cancer and injected tumor-specific CTLs that silenced RGS1.
This study found that the infusion silenced RGS1 The CTL can effectively increase the local infiltration of CTL in the tumor, thereby enhancing its killing function and significantly reducing the tumor
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On the other hand, in order to simulate the patient’s tumor microenvironment to the greatest extent and avoid allogeneic reactions, the study selected a human tumor xenograft (Patient-derived xenograft, PDX) model, and used immune checkpoint inhibitor PD alone or in combination.
-L1 monoclonal antibody and adoptive cell therapy to simulate the process of patient immunotherapy
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This study found that the effect of PD-L1 inhibitor alone is not good, and the infusion of T cell therapy that silences RGS1 can significantly increase the tumor infiltrating T cells, turning "cold tumors" into "hot tumors", and then combined with PD-L1 Inhibitors can achieve better therapeutic effects
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It is reported that Academician Song Erwei and Researcher Su Shicheng are the co-corresponding authors of this paper, and Dr.
Huang Di, postdoctoral fellow Chen Xueman, and Dr.
Zeng Xin are the co-first authors of this paper
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