Tumor Cell–Intrinsic c-Myb Upregulation Stimulates Antitumor Immunity in a Murine Colorectal Cancer Model

The transcription factor c-Myb is overexpressed in many different types of solid tumors, including colorectal cancer. However, its exact role in tumorigenesis is unclear. In this study, we show that tumor-intrinsic c-Myb expression in mouse models of colon cancer and melanoma suppresses tumor growth. Although no differences in proliferation, apoptosis, and angiogenesis of tumors were evident in tumors with distinct levels of c-Myb expression, we observed changes in intratumoral immune cell infiltrates. MC38 tumors with upregulated c-Myb expression showed increased numbers of CD103+ dendritic cells and eosinophils, but decreased tumor-associated macrophages (TAM). Concomitantly, an increase in the number of activated cytotoxic CD8+ T cells upon c-Myb upregulation was observed, which correlated with a pro-inflammatory tumor microenvironment and increased numbers of M1 polarized TAMs. Mechanistically, c-Myb upregulation in immunogenic MC38 colon cancer cells resulted in enhanced expression of immunomodulatory genes, including those encoding β2-microglobulin and IFNβ, and decreased expression of the gene encoding the chemokine receptor CCR2. The increased numbers of activated cytotoxic CD8+ T cells contributed to tumor growth attenuation. In poorly immunogenic CT26, LLC, and B16-BL6 tumor cells, c-Myb upregulation did not affect the immunomodulatory gene expression. Despite this, c-Myb upregulation led to reduced B16-BL6 tumor growth but it did not affect tumor growth of CT26 and LLC tumors. Altogether, we postulate that c-Myb functions as a tumor suppressor in a tumor cell–type specific manner and modulates antitumor immunity

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages.

Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2-positive monocytes. Gene expression profiling of macrophages from pre-tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor-associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody-mediated depletion of macrophages, which strongly suppressed activin-induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation

Memeli hücrelerinde otofajinin moleküler mekanizması

Mayadan insana kadar evrimsel olarak korunmuş bir mekanizma olan makrootofaji (bundan sonra otofaji), hücreleri açlıktan ve buna bağlı streslerden korumakta ve makromolekülleri enerji sağlamak için kullanılabilecek olan yapı taşlarına indirgemektedir. Otofaji, bir parça sitoplazma yığınını, organelleri (örneğin mitokondri ve peroksizomlar), agregat oluşturmaya eğilim gösteren proteinleri ve enfeksiyöz ajanları otofagozomlar olarak adlandırılan çift-membranlı veziküllerle lizozomlara taşıyan hücre içi degredasyon yoludur. Memeli sistemi üzerine yapılan çalışmalar, sağlık ve hastalıkta otofajinin diğer önemli rollerini göstermiştir. Klinik öncesi hem nörodejeneratif hem de enfeksiyöz hastalıklarla ilgili hayvan modellerinde yapılan araştırmalar, otofaji upregülasyonunun, demans formları (tau'nun neden olduğu), Parkinson hastalığı (α-sinüklein) ve Huntington hastalığı (mutant huntingtin) gibi çeşitli nörodejeneratif hastalıklara neden olan agregata eğilimli intrasitoplazmik proteinlerin degradasyonunda; Salmonella typhi ve Mycobacterium tuberculosis gibi patojenik ajanlardan kaynaklanan belli bulaşıcı hastalıklara karşı korunmada önemli bir rol oynadığını göstermiştir. Fare hematopoietik kök hücrelerin (HSCs) devamlılığının sürdürülmesinde gerekliliği vurgulanan otofaji, fonksiyonelliği bozulduğunda HSC'leri normalden pre-lökemik bir duruma geçirmektedir. Mutasyonlar veya önemli otofaji regülatörlerinin ifadelerinin azalması nedeniyle otofajik aktivitede gerçekleşen düşüş, pre-lösemi gelişimini desteklerken, bu mekanizmanın tedavide kullanılan ajanlarla yeniden etkinleştirilmesi hastalığın nüksetmesine yol açmaktadır. Otofaji aktivasyon düzeyi, kanser progresyonu ile anabolik ve katabolik işlemlerde üstlendiği rollerden dolayı obezite ve metabolik hastalıklarda önemli rol oynamaktadır. Otofajinin sağlıkta ve çeşitli hastalıkların patogenezindeki moleküler mekanizmalarına ilişkin çalışmaların sayısı gün geçtikçe artmaktadır. Bu derlemede, memeli hücrelerinde gerçekleşen otofaji ve moleküler mekanizması hakkında genel bir bakış sunulması ve bilgi verilmesi amaçlanmıştır

Interleukin-2–based therapies in cancer

Molecular insights into the mechanism of beneficial and adverse effects of interleukin-2 (IL-2) have resulted in the development of improved IL-2 formulations with IL-2 receptor bias and tissue-targeting properties. Several of these compounds are currently in clinical development and are ushering IL-2 therapy into the current era of cancer immunotherapy

Epigenetic mechanisms of tumor resistance to immunotherapy

The recent impact of cancer immunotherapies has firmly established the ability and importance of the immune system to fight malignancies. However, the intimate interaction between the highly dynamic tumor and immune cells leads to a selection process driven by genetic and epigenetic processes. As the molecular pathways of cancer resistance mechanisms to immunotherapy become increasingly known, novel therapeutic targets are being tested in combination with immune-stimulating approaches. We here review recent insights into the molecular mechanisms of tumor resistance with particular emphasis on epigenetic processes and place these in the context of previous models

Demineralization of Turkish Tosya lignite coal by boric acid leaching

<p>Boric acid is a weak inorganic acid type which is generally being used in glass, ceramics, detergents, agriculture, nuclear energy, and medicine fields, which has white crystal color and which can easily dissolve in water. Boric acid is being produced from colemanite which is a boron mineral having wide reserves in Turkey. In recent years, intense studies have been performed on the alternative usage areas of boric acid in Turkey. In this study, boric acid was used as a leaching reagent for the demineralization of coal with high ash content. For the accurate determination of the success of boric acid in dissolving mineral matter, first a series of leaching tests were performed with boric acid, and then studies for removing mineral matter with strong acids such as <b>hydrofluoric acid (</b>HF), HCl, and H₂SO₄ were performed.</p

An IL-2-grafted antibody immunotherapy with potent efficacy against metastatic cancer

Modified interleukin-2 (IL-2) formulations are being tested in cancer patients. However, IL-2 immunotherapy damages IL-2 receptor (IL-2R)-positive endothelial cells and stimulates IL-2Rα (CD25)-expressing lymphocytes that curtail anti-tumor responses. A first generation of IL-2Rβ (CD122)-biased IL-2s addressed some of these drawbacks. Here, we present a second-generation CD122-biased IL-2, developed by splitting and permanently grafting unmutated human IL-2 (hIL-2) to its antigen-binding groove on the anti-hIL-2 monoclonal antibody NARA1, thereby generating NARA1leukin. In comparison to hIL-2/NARA1 complexes, NARA1leukin shows a longer in vivo half-life, completely avoids association with CD25, and more potently stimulates CD8$^{+}$ T and natural killer cells. These effects result in strong anti-tumor responses in various pre-clinical cancer models, whereby NARA1leukin consistently surpasses the efficacy of hIL-2/NARA1 complexes in controlling metastatic disease. Collectively, NARA1leukin is a CD122-biased single-molecule construct based on unmutated hIL-2 with potent efficacy against advanced malignancies

The Histone Methyltransferase Ezh2 Controls Mechanisms of Adaptive Resistance to Tumor Immunotherapy

Immunotherapy and particularly immune checkpoint inhibitors have resulted in remarkable clinical responses in patients with immunogenic tumors, although most cancers develop resistance to immunotherapy. The molecular mechanisms of tumor resistance to immunotherapy remain poorly understood. We now show that induction of the histone methyltransferase Ezh2 controls several tumor cell-intrinsic and extrinsic resistance mechanisms. Notably, T cell infiltration selectively correlated with high EZH2-PRC2 complex activity in human skin cutaneous melanoma. During anti-CTLA-4 or IL-2 immunotherapy in mice, intratumoral tumor necrosis factor-α (TNF-α) production and T cell accumulation resulted in increased Ezh2 expression in melanoma cells, which in turn silenced their own immunogenicity and antigen presentation. Ezh2 inactivation reversed this resistance and synergized with anti-CTLA-4 and IL-2 immunotherapy to suppress melanoma growth. These anti-tumor effects depended on intratumorally accumulating interferon-γ (IFN-γ)-producing PD-1low CD8+ T cells and PD-L1 downregulation on melanoma cells. Hence, Ezh2 serves as a molecular switch controlling melanoma escape during T cell-targeting immunotherapies

Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species

Stimulation of regulatory T (Treg) cells holds great promise for the treatment of autoimmune, chronic inflammatory, and certain metabolic diseases. Recent clinical trials with low-dose interleukin-2 (IL-2) to expand Treg cells led to beneficial results in autoimmunity, but IL-2 immunotherapy can activate both Treg cells and pathogenic T cells. Use of IL-2 receptor α (IL-2Rα, CD25)-biased IL-2/anti-IL-2 antibody complexes improves IL-2 selectivity for Treg cells; however, the mechanism of action of such IL-2 complexes is incompletely understood, thus hampering their translation into clinical trials. Using a cell-based and dynamic IL-2R platform, we identified a particular anti-human IL-2 antibody, termed UFKA-20. When bound to UFKA-20, IL-2 failed to stimulate cells expressing IL-2Rβ (CD122) and IL-2Rγ (CD132), unless these cells also expressed high amounts of CD25. CD25 allowed IL-2/UFKA-20 complexes to bind, and binding to CD25 in the presence of CD122 and CD132 was followed by rapid dissociation of UFKA-20 from IL-2, delivery of IL-2 to CD122 and CD132, and intracellular signaling. IL-2/UFKA-20 complexes efficiently and preferentially stimulated CD4+ Treg cells in freshly isolated human T cells ex vivo and in mice and rhesus macaques in vivo. The crystal structure of the IL-2/UFKA-20 complex demonstrated that UFKA-20 interfered with IL-2 binding to CD122 and, to a lesser extent, also CD25. Together, we translated CD25-biased IL-2 complexes from mice to nonhuman primates and extended our mechanistic understanding of how CD25-biasing anti-human IL-2 antibodies work, which paves the way to clinical trials of CD25-biased IL-2 complexes