Targeting tumor-resident mast cells for effective anti-melanoma immune responses

Kaesler, Susanne; Wölbing, Florian; Kempf, W.; Skabytska, Yuliya; Köberle, Martin; Volz, Thomas; Sinnberg, Tobias; Amaral, Teresa; Möckel, Sigrid; Yazdi, Amir S.; Metzler, Gisela; Schaller, Martin; Hartmann, Karin; Weide, Benjamin; Garbe, Claus; Rammensee, Hans‐Georg; Röcken, Martin; Biedermann, Tilo

doi:10.1172/jci.insight.125057

Cited by 40 publications

(50 citation statements)

References 64 publications

(63 reference statements)

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“…We found that Tα1 promoted the tumor infiltration of CD8 + cells, thus increasing the tumor immunoscore, now considered a marker of improved overall survival in response to ICI ( Pages et al, 2018 ; Kumpers et al, 2019 ; Angell et al, 2020 ). The mechanisms at the basis of these effects may include the production of CXCL10, a chemokine recognized for its role in the recruitment of tumor-infiltrating lymphocytes being required for antitumor immune responses following immune checkpoint blockade ( House et al, 2020 ) and acting as a biomarker for long-term survival of melanoma patients ( Kaesler et al, 2019 ). Indeed, not only DC differentiated from bone marrow precursors in the presence of Tα1 expressed high levels of CXCL10 but CXCL10 was also expressed in the tumor microenvironment in response to Tα1.…”

Section: Discussionmentioning

confidence: 99%

Thymosin α1 protects from CTLA-4 intestinal immunopathology

et al. 2020

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The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor–induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1–dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8+ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

Thymosin α1 protects from CTLA-4 intestinal immunopathology

et al. 2020

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“…Furthermore, the activation of mast cells can be boosted by molecules produced by bacteria, such as δ-toxin released by S.aureus during atopic dermatitis 33,34 . The relationship between mast cells and microbiota is particularly interesting due to the microbiota capability to activate immune cells within the tumor microenvironment, and the potential exploiting of bacterial derived molecules to boost tumor immune defense 35 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of skin surface and dermal microbiota in dogs with mast cell tumor

Zamarian

Catozzi

Cuscó³

et al. 2020

Sci Rep

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The skin microbiota interacts with the host immune response to maintain the homeostasis. Changes in the skin microbiota are linked to the onset and the progression of several diseases, including tumors. We characterized the skin surface and dermal microbiota of 11 dogs affected by spontaneous mast cell tumor (MCT), using skin contralateral sites as intra-animal healthy controls. The microbial profile differed between healthy and tumor skin surfaces and dermis, demonstrating that the change in microbiota composition is related to the presence of MCT. The number of observed taxa between MCT and healthy skin surfaces was detected, showing a decrease in number and heterogeneity of taxa over the skin surface of MCT, at both inter-and intra-individual level. Preliminary data on bacterial population of MCT dermis, obtained only on three dogs, demonstrated an intra-individual reduction of taxa number when compared to the skin surface. Taxonomy reveals an increase of Firmicutes phylum and Corynebacteriaceae family in MCT skin surface when compared to the healthy contralateral. In conclusion, we demonstrate that microbial population of skin surface and dermis is related to mast cell tumor. Our study provides the basis for future investigations aiming to better define the interaction between mast cell tumors, microbiota and host immune response. The epidermis, or skin surface, provides the external layer to the three parts of the skin, the inner layer being the dermis and hypodermis. The epidermis is regarded as a microenvironment containing a rich eukaryotic and prokaryotic population, currently defined as the microbiota 1,2 , which plays a role as protective and immunological barrier 3. Culture-independent determination of the microbial profile of dog skin surface has been recently determined, showing that microbiota largely differs between body sites 4. The skin microbiota is modulated by extrinsic (e.g. diet, environment) and intrinsic (e.g. genetics) factors 5 , and is not only limited to skin surface but also extends to the dermis 6. Remarkably, bacteria detected within the human healthy dermis and subcutaneous adipose tissue showed a different microbial population profile as compared to the skin surface 7. Four major phyla-namely Actinobacteria, Firmicutes, Proteobacteria, Bacteroidetes-and four major families-namely Corynebacteriaceae, Propionibacteriaceae, Staphylococcaceae, Micrococcaceae-dominate both canine 2 and human epidermal surfaces 1. Given the limited number of studies, the definition of canine skin "healthy microbiota" is still debated. Changes in microbiota composition are associated with the development of skin disorders in both humans and dogs 8,9 , as previously reported dermatitis 10 in dogs. The defensive capability of skin is supported by healthy and balanced microbiota through the interaction with the residing immune cells in the cutis 9,11,12. Due to their localization within the skin, mast cells are in close contact with the bacterial population 13. The activities of mast cells may be amplified...

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“…Targeting MCs to improve therapeutic strategies was also suggested in a pre-clinical model of melanoma, where Kaesler and colleagues identified MCs accumulating in and around melanomas after anti-CTLA-4 treatment and showed that effective melanoma immune control was dependent on LPS-activated MCs that secreted CXCL10, which promoted the recruitment of effector T cells. They highlighted a new way to target MCs and to involve them in the tumor immune defense [ 257 ].…”

Section: Mast Cellsmentioning

confidence: 99%

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

Domagala

Laplagne

Leveque

et al. 2021

Cancers

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Interactions between malignant cells and neighboring stromal and immune cells profoundly shape cancer progression. New forms of therapies targeting these cells have revolutionized the treatment of cancer. However, in order to specifically address each population, it was essential to identify and understand their individual roles in interaction between malignant cells, and the formation of the tumor microenvironment (TME). In this review, we focus on the myeloid cell compartment, a prominent, and heterogeneous group populating TME, which can initially exert an anti-tumoral effect, but with time actively participate in disease progression. Macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells, eosinophils, and basophils act alone or in concert to shape tumor cells resistance through cellular interaction and/or release of soluble factors favoring survival, proliferation, and migration of tumor cells, but also immune-escape and therapy resistance.

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Targeting tumor-resident mast cells for effective anti-melanoma immune responses

Cited by 40 publications

References 64 publications

Thymosin α1 protects from CTLA-4 intestinal immunopathology

Thymosin α1 protects from CTLA-4 intestinal immunopathology

Characterization of skin surface and dermal microbiota in dogs with mast cell tumor

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

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