Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer

Chen, Yuru; Sun, Jiazheng; Luo, Yachan; Liu, Jiazhou; Wang, **aoyu; Feng, Rui; Huang, **g; Du, Huimin; Li, Qin; Tan, **xiang; Ren, Guosheng; Wang, **aoyi; Li, Hongzhong

doi:10.1186/s12967-022-03807-8

Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer

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Published: 23 December 2022

Volume 20, article number 615, (2022)
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Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer

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Yuru Chen^1,2^na1,
Jiazheng Sun^1,2^na1,
Yachan Luo³,
Jiazhou Liu^1,2,
**aoyu Wang^1,2,
Rui Feng^1,2,
**g Huang⁴,
Huimin Du⁵,
Qin Li⁶,
**xiang Tan²,
Guosheng Ren^1,2,
**aoyi Wang² &
…
Hongzhong Li ORCID: orcid.org/0000-0003-1136-5235^1,2

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Abstract

Background

Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic.

Methods

Here, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival.

Results

Our bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8⁺ T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4⁺ T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects.

Conclusions

Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy.

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Introduction

Breast cancer is a complex disease associated with high morbidity and mortality rates [1]. It is classified into triple-negative breast cancer (TNBC), hormone receptor positive (HR +) with estrogen (ER) and/or progesterone (PR) receptor, and human epidermal receptor 2 positive (HER2 +) [2]. Compared with HR + subtype, which is characterized by low tumor-infiltrating lymphocytes (TILs) infiltration, TNBC and HER2 + subtypes are associated with high infiltration of TILs [3, 4]. Notably, higher TIL levels are associated with improved prognosis and decreased risk of relapse and death [5, 6]. Immune checkpoint blockade (ICB) therapies targeting programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have produced enormous clinical efficacy in multiple cancer patients [7]. Increasing studies exhibit that ICB has a clinical response against advanced breast cancer [8,9,10]. Unfortunately, only a small proportion of patients (less than 20%) with breast cancer can get benefit from ICB therapy [8]. Thus, how to surmount the resistance to immunotherapy and improve clinical efficacy in breast cancer is worth further exploration.

Multiple factors are correlated with therapeutic efficacy of ICB in breast cancer, including the degree of cytotoxic T lymphocyte (CTL) infiltration, tumor mutation burden, the expression level of immune checkpoint and immunosuppressive factors in tumor microenvironment (TME) [9, 10]. Increasing evidence indicates that immunological composition and functional status of TME have a critical role in ICB resistance [10, 11]. The infiltration of immune cells, such as T cell, myeloid-derived suppressor cell (MDSC), and tumor-associated macrophage (TAM) in TME, can affect therapeutic efficacy of ICB therapy. Tumor cells can co-evolve with immune cells and evolve a variety of strategies to escape immune destruction [12,13,14]. T-helper 2 (Th2) cell, a vital component of TME, plays a central role in type-2 immune responses (“humoral immunity”) and up-regulates antibody production to fight extracellular tissues [15, 16]. Th2 cell-derived cytokines including interleukin-4 (IL-4), IL-5, and IL-13 underlie the inappropriate immune response, and lead to anaphylactic diseases such as asthma, chronic rhinitis, atopic dermatitis, and certain types of gut disorders [17,18,19]. It is indicated that Th2 cell plays a controversial role in cancer development. It is shown that high infiltration of Th2 cell could cause the epigenetic reprogramming of tumor cells and suppress breast tumorigenesis [20]. Additionally, Th2 cells are positively involved in tumor regression by triggering an inflammatory immune response [21]. In contrast, several lines of evidence support that the initiation of local Th2 inflammation could foster an immunosuppressive microenvironment and aid tumor progression [22,23,24]. Therefore, the relationship between Th2 and immune evasion in breast cancer remains enigmatic, which needs further in-depth investigation.

Allergies are abnormal, Th2-biased immune responses against innocuous environmental antigens [25]. Our previous study found that the allergy mediator histamine could suppress tumor growth, and induce immunotherapy resistance via binding to histamine receptor H1 on macrophages, and anti-histamine therapy could synergistically enhance efficacy of ICB therapy [Full size image

Considering adverse effects may cause intolerance in therapy procedures and negatively affect its clinical efficacy, we next evaluated the adverse effects of IPD in the mouse models [43, 44]. The H&E staining showed that solid organ injury of breast cancer was not enhanced after IPD treatment. Compared with ICB therapy, IPD would not increase the immune-related adverse events associated with anti-CTLA-4 in combination therapy (Additional file 7: fig. S7A). Moreover, compared with vehicle-treated group, IPD treatment did not exacerbate the liver damage and impair renal and cardiac functions, and had no haematotoxin effect and bone marrow suppression based on blood test (Additional file 7: Fig. S7B, C). Together, our results implied that related adverse event was no presented after administration of IPD in vivo.

Discussion

The efficacy of ICB therapy has been widely evaluated in breast cancer. Unfortunately, most clinical research shows that cancer patients get limited benefit from ICB [45]. Thus, increasing combination therapies are evaluated to surmount the resistance to immunotherapy and improve clinical efficacy [46, 47]. Accumulating evidences indicate that the immunosuppressive TME inhibits ICB response and are commonly associated with poor prognosis of breast cancer patients [48]. Therefore, to explore potential therapies targeting TME might help reverse immunotherapy resistance. Th2 cells are an important immune component in TME [49, 50]. Several evidence showed that Th2 cell infiltration in TME could facilitate tumor growth [51]. The complex cytokine cross-talk of Th2 cell in TME was correlated with worse prognosis in cancer [52]. Here, our study found a strong negative correlation between Th2 cell infiltration and the infiltration and function of CD8⁺ T cells in breast cancer, suggesting that Th2 cells might be an obstacle for antitumor immunity. Consistently, targeting IL-4 and IL-5 antibodies was reported to suppress tumor progression in multiple cancers, showing targeting Th2 cytokines might be a potential therapy for tumor treatment [53,54,55]. However, Th2-mediated immunity is a complicated process with multiple cytokines involved. The efficacy of targeting single cytokine remains limited. Therefore, more effective agents targeting Th2-mediated immunity were also needed for investigation.

IPD, an immunoregulatory compound, has the potential to treat anaphylactic diseases [56]. Increasing studies show that IPD inhibits the secretion of Th2 cell-derived IL-4 and IL-5 and is thus defined as a Th2 cytokine inhibitor [56, 57]. Here, we demonstrated that IPD indeed increased the ratio of Th1/Th2 cells in breast cancer and suppressed the secretion of IL-4 in both peripheral blood and tumors. T cell infiltration and activation in tumor immune microenvironment are important for antitumor effects in breast cancer [11]. It is demonstrated that Th2 cells promote tumor growth by affecting T cell infiltration [58]. Our data validated that targeting Th2-mediated immunity by IPD could significantly activate the host immune response and inhibit tumor growth in breast cancer. IPD could remarkably increase the infiltration and proliferation of cytotoxic CD8⁺ T cells, and enhance the cytotoxic cytokine secretion of CD8⁺ T cells, indicating that antitumor T cell immunity was activated when Th2 cytokines were inhibited. Additionally, accumulating evidence suggests that targeting macrophages has emerged as a potential approach against ICB resistance [59, 60]. It has been acknowledged that Th2 cells induce macrophages polarized to pro-tumor M2 phenotype through the secretion of IL-4 and IL-13 [42]. Our study found that targeting Th2-mediated immunity by IPD could polarize TAMs to antitumor M1 macrophage, suggesting that blocking Th2-mediated immunity could alleviate TAMs-mediated immunosuppression. Moreover, Th2-type immune responses are usually accompanied by an increase in the infiltration of MDSCs and Tregs which contributes to pro-tumor immunity [61]. We also demonstrated that IPD decreased the infiltration of MDSCs and Tregs in breast cancer. In conclusion, targeting Th2-mediated immunity by IPD elicited an antitumor immune response against breast cancer via modulating the global immune landscape.

Furthermore, our study here showed that IPD targeting Th2-mediated immunity could enhance ICB response via promoting antitumor activity of cytotoxic CD8⁺ T cells in breast cancer. In addition, the global immune landscape was also reshaped after combinational therapy. The total CD4⁺ T cell infiltration was increased, and MDSCs and TAMs were further decreased in combinational therapy compared with single drug treatment and control group. Notably, apart from the suppression of IPD on tumor growth in vivo, we found that IPD treatment alone inhibited lung metastasis of tumor cells compared with vehicle-treated group in 4T1 spontaneous metastasis mouse model, and IPD in combination with ICB further enhanced this effect. Since the transwell migration assay showed no significant change about metastatic potential of tumor cells after IPD treatment, we speculated that IPD might exert the inhibitory effect on lung metastasis by regulating tumor immune environment of primary or metastatic tumors. Our previous study demonstrated that targeting histamine/HRH1 axis only partially reversed allergy-induced immunotherapy resistance [26]. This study supported that Th2-mediated immunity might also contribute to allergy-induced immunotherapy resistance and targeting Th2-mediated immunity would help reverse this resistance, which warrants further investigation. In addition, immune-related adverse event happens frequently in ICB therapy and affects healthy tissues in the body [43, 44], which is an essential factor to limit its clinical application. Here, we found that IPD had been well tolerated and would not exacerbate systemic damage of ICB in mouse models. Together, our findings implied that targeting Th2-mediated immunity might be a promising therapeutic approach in combination with ICB in clinical therapies.

Conclusions

Our study confirms that pharmaceutical inhibition of Th2-mediated immunity by IPD could elicit an antitumor immune response against breast cancer by enhancing the antitumor activity of cytotoxic CD8⁺ T and modulating the global immune landscape of TME. Furthermore, targeting Th2-mediated immunity by IPD enhances therapeutic responses to ICB, which warrants prospectively exploring therapeutic drugs as adjuvant agents for combinatorial immunotherapy.

Availability of data and materials

Publicly available datasets were analyzed in study. These can be found in the Cancer Genome Atlas (https://portal.gdc.cancer. gov/) and Cibioportal (https://www.cbioportal.org).

Abbreviations

ICB:: Immune checkpoint blockade
Th2:: T-helper 2
TME:: Tumor microenvironment
IPD:: Suplatast tosilate
CTL:: Cytotoxic T lymphocyte
TNBC:: Triple-negative breast cancer
HR:: Hormone receptor
ER:: Estrogen receptor
PR:: Progesterone receptor
TILs:: Tumor-infiltrating lymphocytes
PD-1:: Programmed death 1
PD-L1:: Programmed death ligand 1
CTLA-4:: Cytotoxic T lymphocyte-associated antigen 4
MDSC:: Myeloid-derived suppressor cell
TAM:: Tumor-associated macrophage
IL-4:: Interleukin-4
TCGA:: The Cancer Genome Atlas
METABRIC:: Molecular Taxonomy of Breast Cancer International Consortium
GEO:: Gene Expression Omnibus
Fges:: Functional gene expression signatures
TIMER:: Tumor Immune Estimation Resource
TIDE:: Tumor Immune Dysfunction and Exclusion
IF:: Immunofluorescence
CyTOF:: Mass cytometry
Treg:: Regulatory T cells
MHCII:: Histocompatibility complex class II
NK cells:: Natural killer cells

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Acknowledgements

Publicly available data from TCGA-BRCA, MTABRIC, TIDE, and TIMER were utilized in the study, and we would like to thank the authors for making their data obtainable. We thank all the lab members for suggestions.

Funding

This work was supported by the National Natural Science Foundation of China (NO. 82173166, 81472475, and 82273282), Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0015 and 2022NSCQ-MSX0825), Chongqing medical scientific research project (NO.2021MSXM033) and CQMU Program for Youth Innovation in Future Medicine (NO. W0094).

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Yuru Chen and Jiazheng Sun have contributed equally to this work

Authors and Affiliations

Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Yuru Chen, Jiazheng Sun, Jiazhou Liu, **aoyu Wang, Rui Feng, Guosheng Ren & Hongzhong Li
Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Yuru Chen, Jiazheng Sun, Jiazhou Liu, **aoyu Wang, Rui Feng, **xiang Tan, Guosheng Ren, **aoyi Wang & Hongzhong Li
Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Yachan Luo
Department of Respiratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
**g Huang
Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Huimin Du
Department of Oncology, Bei**g Friendship Hospital, Capital Medical University, Bei**g, 100050, China
Qin Li

Authors

Yuru Chen
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Jiazheng Sun
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Yachan Luo
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Jiazhou Liu
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**aoyu Wang
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Rui Feng
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**g Huang
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Huimin Du
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Qin Li
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**xiang Tan
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Guosheng Ren
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**aoyi Wang
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Hongzhong Li
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Contributions

Conceptualization: YRC, JZS, YCL, HZL, XYW. Flow and mass cytometry analysis: YRC, JZS, HZL. Performed in vitro assays: YRC. Performed in vivo studies: YRC, JZS, JZL, XYW, RF, QL. IF and histopathology: YRC. Writing manuscript: YRC, JZS, HZL. Resources and conceptual: HZL, XYW, GSR, HMD, JH, JXT. Guarantors: YRC, JZS, YCL, HZL, GSR. Manuscript review and approval: All authors. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to **aoyi Wang or Hongzhong Li.

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Animal experiments are approved by the Biomedical Ethics Committee of Chongqing Medical University. There is no human subject participation.

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The authors have declared that no competing interest exists.

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Supplementary Information

Additional file 1.

Figure S1 Correlations between Th2 cell proportion and T cell infiltration and dysfunction in TCGA database.

Additional file 2.

Figure S2 IPD increases the infiltration of CD4⁺ T cells and promotes Th2 to Th1 switch.

Additional file 3.

Figure S3 IPD does not regulate the proliferation and migration of tumor cells in vitro.

Additional file 4.

Figure S4 IPD enhances the antitumor effect of CD8⁺ T cells.

Additional file 5.

Figure S5 IPD reshapes the immune landscape in the TME.

Additional file 6.

Figure S6 IPD synergizes with anti-CTLA-4 treatment in breast cancer.

Additional file 7.

Figure S7 IPD has no significant adverse reaction.

Additional file 8.

Figure S8 Gating strategy for flow cytometry assays.

Additional file 9.

Additional materials and methods.

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Chen, Y., Sun, J., Luo, Y. et al. Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer. J Transl Med 20, 615 (2022). https://doi.org/10.1186/s12967-022-03807-8

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Received: 21 October 2022
Accepted: 02 December 2022
Published: 23 December 2022
DOI: https://doi.org/10.1186/s12967-022-03807-8

Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer

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