Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma

Bararia, Deepak; Hildebrand, Johannes Adrian; Stolz, Sebastian; Haebe, Sarah; Alig, Stefan; Trevisani, Christopher; Osorio‐Barrios, Francisco; Bartoschek, Michael D.; Mentz, Michael; Pastore, Alessandro; Gaitzsch, Erik; Heide, Michael; Jurinović, Vindi; Rautter, Katharina; Gunawardana, Jay; Sabdia, Muhammed B.; Szczepanowski, Monika; Richter, Julia; Klapper, Wolfram; Louissaint, Abner; Ludwig, Christina; Bultmann, Sebastian; Leonhardt, Heinrich; Eustermann, Sebastian; Hopfner, Karl‐Peter; Hiddemann, Wolfgang; Bergwelt‐Baildon, Michael von; Steidl, Christian; Kridel, Robert; Tobin, Joshua W.D.; Gandhi, Maher K.; Weinstock, David M.; Schmidt-Supprian, Marc; Sárosi, Menyhárt B.; Rudelius, Martina; Passerini, Verena; Mautner, Josef; Weigert, Oliver

doi:10.1016/j.celrep.2020.107522

Cited by 54 publications

(72 citation statements)

References 66 publications

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“…The Y132D mutation results in a higher autocatalytic conversion from the inactive proform to active CatS. In a CatS Y132D transgenic mouse model of follicular lymphoma, they observed increased cancer growth versus wild-type controls and an increase of the tumor-suppressive CD4+ Treg over cytotoxic CD8+ T cells infiltrating the tumor [1]. In confirmation, Dheilly et al showed that in patients with non-Hodgkin lymphoma, the same activating CatS Y132D mutation in malignant B cells is promoted, and its inhibition abrogated lymphoma growth via enhancing the cytotoxic CD8+ T-cell response and attenuating the expansion of CD4+ Treg [3].…”

Section: Cathepsin Smentioning

confidence: 99%

“…The expression and activity of these cathepsins is generally upregulated in (chronic) inflammation and in cancers. Consequently, they are overexpressed in tumors, prominently for CatB and CatS, including in follicular lymphoma, gastric, colon, brain, breast, and pancreatic cancer [1,3,6]. Overall, most but not all of these cathepsin-mediated mechanisms result in enhanced ECM turnover and angiogenesis, clearing the way for tumor expansion, securing the cancers' nutrient supply, and, most notably, in suppressing the T-cell induced anti-cancer immune response that is located in the TME.…”

Section: Cysteine Cathepsins In Tumor Progressionmentioning

confidence: 99%

“…Chronic diseases, especially autoimmunity, organ fibrosis, and cancer are usually characterized by dysregulated proteolysis that contributes to disease progression. The lysosomal proteases are involved in protein catabolism and some of them, prominently several cysteine cathepsins, are overexpressed in tumors [1][2][3]. This makes them attractive targets in the development of new anti-cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

“…(a) CatS is overexpressed in many tumors and favors the MHC-II pathway, leading to an increase of CD4+ T cells instead of cytotoxic CD8+ T cells. (b) The inhibition of CatS can enhance the anti-tumor immune response by promoting cytotoxic CD8+ T cells instead of CD4+ T cells [1,3].…”

Section: Introductionmentioning

confidence: 99%

“…Cysteine cathepsins comprise a family of 11 proteases, of which 5 have been repeatedly implicated in the progression of solid cancers (cathepsins B, H, K, L, and S) [ 4 ]. Among these, cathepsin S (CatS) has emerged as an attractive potential target whose inhibition promises to address the immune-suppressive milieu of the tumor microenvironment (TME) [ 1 , 3 , 4 ] due to its role in the polarization of antigen-presenting cells (APC) from an M1 toward a tumor-favoring M2-phenotype. M2-type APC support myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), favoring the expansion of tolerogenic regulatory T cells (Treg) cells instead of cytotoxic CD8+ T cells, which leads to an immune suppression in favor of tumor cells ( Figure 1 ) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery

Fuchs

Meta

Schuppan

et al. 2020

Cells

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Cathepsin S (CatS) is a secreted cysteine protease that cleaves certain extracellular matrix proteins, regulates antigen presentation in antigen-presenting cells (APC), and promotes M2-type macrophage and dendritic cell polarization. CatS is overexpressed in many solid cancers, and overall, it appears to promote an immune-suppressive and tumor-promoting microenvironment. While most data suggest that CatS inhibition or knockdown promotes anti-cancer immunity, cell-specific inhibition, especially in myeloid cells, appears to be important for therapeutic efficacy. This makes the design of CatS selective inhibitors and their targeting to tumor-associated M2-type macrophages (TAM) and DC an attractive therapeutic strategy compared to the use of non-selective immunosuppressive compounds or untargeted approaches. The selective inhibition of CatS can be achieved through optimized small molecule inhibitors that show good pharmacokinetic profiles and are orally bioavailable. The targeting of these inhibitors to TAM is now more feasible using nanocarriers that are functionalized for a directed delivery. This review discusses the role of CatS in the immunological tumor microenvironment and upcoming possibilities for a nanocarrier-mediated delivery of potent and selective CatS inhibitors to TAM and related APC to promote anti-tumor immunity.

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Section: Cathepsin Smentioning

confidence: 99%

Section: Cysteine Cathepsins In Tumor Progressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery

Fuchs

Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α‐Fluorovinylsulfones and α‐Sulfonates as Potential Immunomodulators in Cancer

Fuchs

Vulnerabilities in the tumor and microenvironment in follicular lymphoma

Araujo-Ayala

Pérez-Galán

Campo

2021

Hematological Oncology

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Follicular lymphoma (FL) is a paradigm of tumors that require the interaction between tumor and microenvironment cells to foster their development from initial steps to progression. Recent large‐scale genome studies have uncovered multiple genetic alterations of FL that influence the microenvironment in two main directions, promoting tumor cell survival and proliferation and facilitating their evasion from immune antitumor signals. Understanding the crosstalk between tumor B‐cells and the microenvironment will facilitate the identification of vulnerabilities that may offer novel targets for treatment of the patients. This review highlights recent findings showing the effect of common genetic mutations modulating the cell composition of the tumor microenvironment and the novel therapeutic perspectives to target these interactions.

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Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma

Cited by 54 publications

References 66 publications

Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery

Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery

Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α‐Fluorovinylsulfones and α‐Sulfonates as Potential Immunomodulators in Cancer

Vulnerabilities in the tumor and microenvironment in follicular lymphoma

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