IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer

Blomberg, Olga; Spagnuolo, Lorenzo; Garner, Hannah; Voorwerk, Leonie; Isaeva, Olga I.; Dyk, Ewald van; Bakker, Noor; Chalabi, Myriam; Klaver, Chris; Duijst, M.; Kersten, Kelly; Brüggemann, Marieke; Pastoors, Dorien; Hau, Cheei-Sing; Vrijland, Kim; Raeven, Elisabeth A.M.; Kaldenbach, Daphne; Kos, Kevin; Afonina, Inna S.; Kaptein, Paulien; Hoes, Louisa R.; Theelen, Wendy; Baas, Paul; Voest, Emile E.; Beyaert, Rudi; Thommen, Daniela S.; Wessels, Lodewyk F.A.; Visser, Karin E. de; Kok, Marleen

doi:10.1016/j.ccell.2022.11.014

Cited by 65 publications

(61 citation statements)

References 90 publications

(161 reference statements)

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“…In CRC, Th2 cells are considered to be the main source of IL-5 in iTME [ 20 ]. In breast cancer, an immune checkpoint blockade increased IL-5 production by CD4+ T cells [ 47 ]. We conducted PCA in the B7H4 positive group on the chosen cluster and we found a positive correlation between PC2 and B7H4 IHC expression.…”

Section: Discussionmentioning

confidence: 99%

B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes

Dawidowicz

Kula

Mielcarska

et al. 2023

Cells

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The immunotherapies based on ICIs in CRC are nowadays limited to microsatellite unstable tumours which are approximately 15% of all CRC cases. There are a few new immune checkpoints belonging to the B7 family, including B7H4. B7H4 expression is associated with so-called “cold tumours”, and its function is linked to the downregulation of various immune cell populations. Our study aimed to investigate whether B7H4 expression is dependent on microsatellite status in CRC and on elucidating the immunological context in which the expression of B7H4 occurs. We enrolled 167 patients in the study. We prepared the homogenates from tumour tissues and healthy adjacent tissue to assess the B7H4 levels and the Bio-Plex Pro Human 48-cytokine panel. We assessed the microsatellite status of the tumour, B7H4 expression, CD8+ T cell population, and the TILs and budding in H + E stained slides by the IHC method. We used an online available database for further exploring the biological characteristics of B7H4. The expression of B7H4 was more frequent in microsatellite stable tumours, and was negatively associated with TILs. B7H4 is positively correlated with antitumour immunosuppressive iTME, thus contributing to the immunosuppressive environment in CRC.

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Section: Discussionmentioning

confidence: 99%

B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes

Dawidowicz

Kula

Mielcarska

et al. 2023

Cells

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“…Such T-cell help is likely multifaceted, including ‘licensing’ DCs; CD4 + T-cell secretion of cytokines (eg, IL-21, IFN-γ); TME reprogramming; or through positive effects of recruited eosinophils on CD8 + T-cell immune surveillance. 36 46 Possibly due to the activity of polio neutralizing antibodies limiting CD4 + T-cell activation by reducing recall antigen availability or persistence, B cells were counterproductive to antitumor effects of polio recall.…”

Section: Discussionmentioning

confidence: 99%

Intratumor childhood vaccine-specific CD4⁺T-cell recall coordinates antitumor CD8⁺T cells and eosinophils

Brown

Beasley

McKay

et al. 2023

J Immunother Cancer

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BackgroundAntitumor mechanisms of CD4+T cells remain crudely defined, and means to effectively harness CD4+T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy.MethodsThe impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+T-cell and B-cell knockout, CD4+T-cell depletion, CD4+T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans.ResultsPrior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy.ConclusionPre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+T-cell help for antitumor CD8+T cells, and implicates eosinophils as antitumor effectors of CD4+T cells.

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“…IL33 facilitates immunosuppressive ( Jovanovic et al, 2014 ), and fibroblast-derived IL33 modifies the immune microenvironment to promote breast cancer growth and metastases ( Shani et al, 2020 ). Induction or recombinant IL-33 enhances immune checkpoint blockade treatment in breast cancer ( Blomberg et al, 2023 ). IFN-γ-driven immunosuppressive pathway has been a target in MUC1-C alone or combination with ICPs treatment for TNBC ( Yamashita et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Development of a risk model to predict prognosis in breast cancer based on cGAS-STING-related genes

et al. 2023

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Background: Breast cancer (BRCA) is regarded as a lethal and aggressive cancer with increasing morbidity and mortality worldwide. cGAS-STING signaling regulates the crosstalk between tumor cells and immune cells in the tumor microenvironment (TME), emerging as an important DNA-damage mechanism. However, cGAS-STING-related genes (CSRGs) have rarely been investigated for their prognostic value in breast cancer patients.Methods: Our study aimed to construct a risk model to predict the survival and prognosis of breast cancer patients. We obtained 1087 breast cancer samples and 179 normal breast tissue samples from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEX) database, 35 immune-related differentially expression genes (DEGs) from cGAS-STING-related genes were systematically assessed. The Cox regression was applied for further selection, and 11 prognostic-related DEGs were used to develop a machine learning-based risk assessment and prognostic model.Results: We successfully developed a risk model to predict the prognostic value of breast cancer patients and its performance acquired effective validation. The results derived from Kaplan-Meier analysis revealed that the low-risk score patients had better overall survival (OS). The nomogram that integrated the risk score and clinical information was established and had good validity in predicting the overall survival of breast cancer patients. Significant correlations were observed between the risk score and tumor-infiltrating immune cells, immune checkpoints and the response to immunotherapy. The cGAS-STING-related genes risk score was also relevant to a series of clinic prognostic indicators such as tumor staging, molecular subtype, tumor recurrence, and drug therapeutic sensibility in breast cancer patients.Conclusion: cGAS-STING-related genes risk model provides a new credible risk stratification method to improve the clinical prognostic assessment for breast cancer.

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IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer

Cited by 65 publications

References 90 publications

B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes

B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes

Intratumor childhood vaccine-specific CD4⁺T-cell recall coordinates antitumor CD8⁺T cells and eosinophils

Development of a risk model to predict prognosis in breast cancer based on cGAS-STING-related genes

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IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer

Cited by 65 publications

References 90 publications

B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes

B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes

Intratumor childhood vaccine-specific CD4+T-cell recall coordinates antitumor CD8+T cells and eosinophils

Development of a risk model to predict prognosis in breast cancer based on cGAS-STING-related genes

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Intratumor childhood vaccine-specific CD4⁺T-cell recall coordinates antitumor CD8⁺T cells and eosinophils