ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung

Schuijs, Martijn J.; Png, Shaun; Richard, Alison F.; Tsyben, Anastasia; Hamm, Grégory; Stockis, Julie; Garcia, Celine; Pinaud, Silvain; Nicholls, Ashley; Ros, Xavier Romero; Su, Jing; Eldridge, Matthew; Riedel, Angela; Serrao, Eva M.; Rodewald, Hans-Reimer; Mack, Matthias; Shields, Jacqueline D.; Cohen, E. Suzanne; McKenzie, Andrew N. J.; Goodwin, Richard J. A.; Brindle, Kevin M.; Marioni, John C.; Halim, Timotheus Y.F.

doi:10.1038/s41590-020-0745-y

Cited by 129 publications

(103 citation statements)

References 68 publications

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“…In the TME, eosinophils have been attributed with immunomodulatory functions since they can interact with various cell types including T cells, 39 , 40 NK cells 41 , 42 and macrophages. 39 , 43 To provide insights into the potential cross-talk between eosinophils and additional immune cell in a given TME, we utilized the TCC database to assess the correlation between the abundance of eosinophils with additional immune cells including CD8 + , CD4 + T cells, NK cells and macrophages in a given TME ( Figure 7 and Supplementary table 7).…”

Section: Resultsmentioning

confidence: 99%

Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations

et al. 2020

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Eosinophils are bone marrow-derived granulocytes that display key effector functions in allergic diseases. Nonetheless, recent data highlight important roles for eosinophils in the tumor microenvironment (TME). Eosinophils have been attributed with pleiotropic and perhaps conflicting functions, which may be attributed at least in part to variations in eosinophil quantitation in the TME. Thus, a reliable, quantitative, and robust method for the assessment of eosinophilic infiltration in the TME is required. This type of methodology could standardize the identification of these cells and promote the subsequent generation of hypothesis-driven mechanistic studies. To this end, we conducted a comprehensive analysis of multiple primary tumors from distinct anatomical sites using a standardized method. Bioinformatics analysis of 10,469 genomically profiled primary tumors revealed that eosinophil abundance within different tumors can be categorized into three groups representing tumors with high, intermediate, and low eosinophil levels. Consequently, eosinophil abundance, as well as spatial distribution, was determined in tissue tumor arrays of six tumors representing all three classifications (colon and esophagus -high; lungintermediate; cervix, ovary, and breast -low). With the exception of breast cancer, eosinophils were mainly localized in the tumor stroma. Importantly, the tumor anatomical site was identified as the primary predictive factor of eosinophil stromal density highlighting a distinction between mucosal-barrier organs versus non-mucosal barrier organs. These findings enhance our understanding of eosinophil diversity in the TME and provide a compelling rationale for future experiments assessing the activity of these cells.

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Section: Resultsmentioning

confidence: 99%

Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations

et al. 2020

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“…Beside the conventional IC presented above, a novel ILC2-dependent metabolic immune checkpoints has recently been uncovered [147]. The authors show that pre-existing type2 inflammation in the lung favors metastatic seeding, in an IL-33 and ILC2-dependent manner.…”

Section: Metabolic Checkpointsmentioning

confidence: 99%

Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

Pesce¹,

Trabanelli

Vito

et al. 2020

Cancers

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Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies.

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“…Although the role of ILC2s is still controversial in cancer, many studies have demonstrated a relationship with cancer metastasis and immunosuppression. For example, as well as MSCs, ILC2s become suppressive upon activation, and the activated ILC2s produce various cytokines, such as IL4, IL5, IL9, and IL13, to impair the anti-tumor immunity, particularly of NK cells [ 111 , 112 ]. Stimulation with TGFβ, IL1β, and IL23 induces the conversion of ILC2s into RORγt + Th17 cells, which are deeply associated with inflammatory and autoimmune diseases, including cancer [ 113 , 114 ].…”

Section: Immune Supporters For Cancer Metastasismentioning

confidence: 99%

Targeting Oncoimmune Drivers of Cancer Metastasis

Kudo-Saito¹,

Ozaki²,

Imazeki³

et al. 2021

Cancers

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Residual metastasis is a major cause of cancer-associated death. Recent advances in understanding the molecular basis of the epithelial–mesenchymal transition (EMT) and the related cancer stem cells (CSCs) have revealed the landscapes of cancer metastasis and are promising contributions to clinical treatments. However, this rarely leads to practical advances in the management of cancer in clinical settings, and thus cancer metastasis is still a threat to patients. The reason for this may be the heterogeneity and complexity caused by the evolutional transformation of tumor cells through interactions with the host environment, which is composed of numerous components, including stromal cells, vascular cells, and immune cells. The reciprocal evolution further raises the possibility of successful tumor escape, resulting in a fatal prognosis for patients. To disrupt the vicious spiral of tumor–immunity aggravation, it is important to understand the entire metastatic process and the practical implementations. Here, we provide an overview of the molecular and cellular links between tumors’ biological properties and host immunity, mainly focusing on EMT and CSCs, and we also highlight therapeutic agents targeting the oncoimmune determinants driving cancer metastasis toward better practical use in the treatment of cancer patients.

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ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung

Cited by 129 publications

References 68 publications

Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations

Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations

Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

Targeting Oncoimmune Drivers of Cancer Metastasis

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