TY  - JOUR
AB  - Metabolic processes are crucial in immune regulation, yet the impact of metabolic heterogeneity on immunological functions remains unclear. Integrating metabolomics into immunology allows the exploration of the interactions of multilayered features in the biological system and the molecular regulatory mechanism of these features. To elucidate such insight in lung squamous cell carcinoma (LUSC), we analyzed 106 LUSC tumor tissues. We performed high-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to obtain spatial metabolic profiles, and immunohistochemistry to detect tumor-infiltrating T lymphocytes (TILs). Unsupervised k-means clustering and Simpson's diversity index were employed to assess metabolic heterogeneity, identifying five distinct metabolic tumor subpopulations. Our findings revealed that TILs are specifically associated with metabolite distributions, not randomly distributed. Integrating a validation cohort, we found that heterogeneity-correlated metabolites interact with CD8+ TIL-associated genes, affecting survival. High metabolic heterogeneity was linked to worse survival and lower TIL levels. Pathway enrichment analyses highlighted distinct metabolic pathways in each subpopulation and their potential responses to chemotherapy. This study uncovers the significant impact of metabolic heterogeneity on immune functions in LUSC, providing a foundation for tailoring therapeutic strategies.
AU  - Wang, Q.
AU  - Sun, N.
AU  - Zhang, C.-Y.
AU  - Kunzke, T.
AU  - Zens, P.*
AU  - Feuchtinger, A.
AU  - Berezowska, S.*
AU  - Walch, A.K.
C1  - 73348
C2  - 57013
CY  - 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
TI  - Metabolic heterogeneity in tumor cells impacts immunology in lung squamous cell carcinoma.
JO  - OncoImmunology
VL  - 14
IS  - 1
PB  - Taylor & Francis Inc
PY  - 2025
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - The major goal of radiotherapy is the induction of tumor cell death. Additionally, radiotherapy can function as in situ cancer vaccination by exposing tumor antigens and providing adjuvants for anti-tumor immune priming. In this regard, the mode of tumor cell death and the repertoire of released damage-associated molecular patterns (DAMPs) are crucial. However, optimal dosing and fractionation of radiotherapy remain controversial. Here, we examined the initial steps of anti-tumor immune priming by different radiation regimens (20 Gy, 4 x 2 Gy, 2 Gy, 0 Gy) with cell lines of triple-negative breast cancer in vitro and in vivo. Previously, we have shown that especially high single doses (20 Gy) induce a delayed type of primary necrosis with characteristics of mitotic catastrophe and plasma membrane disintegration. Now, we provide evidence that protein DAMPs released by these dying cells stimulate sequential recruitment of neutrophils and monocytes in vivo. Key players in this regard appear to be endothelial cells revealing a distinct state of activation upon exposure to supernatants of irradiated tumor cells as characterized by high surface expression of adhesion molecules and production of a discrete cytokine/chemokine pattern. Furthermore, irradiated tumor cell-derived protein DAMPs enforced differentiation and maturation of dendritic cells as hallmarked by upregulation of co-stimulatory molecules and improved T cell-priming. Consistently, a recurring pattern was observed: The strongest effects were detected with 20 Gy-irradiated cells. Obviously, the initial steps of radiotherapy-induced anti-tumor immune priming are preferentially triggered by high single doses - at least in models of triple-negative breast cancer.
AU  - Krombach, J.*
AU  - Hennel, R.*
AU  - Brix, N.*
AU  - Orth, M.*
AU  - Schoetz, U.*
AU  - Ernst, A.*
AU  - Schuster, J.*
AU  - Zuchtriegel, G.*
AU  - Reichel, C.A.*
AU  - Bierschenk, S.*
AU  - Sperandio, M.*
AU  - Vogl, T.*
AU  - Unkel, S.*
AU  - Belka, C.
AU  - Lauber, K.
C1  - 54735
C2  - 45829
CY  - 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
TI  - Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells.
JO  - OncoImmunology
VL  - 8
IS  - 1
PB  - Taylor & Francis Inc
PY  - 2019
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - Mast cells (MC) have been identified in human lung adenocarcinoma (LADC) tissues, but their functional role has not been investigated in vivo. For this, we applied three mouse models of KRAS-mutant LADC to two different MC-deficient mouse strains (cKitWsh and Cpa3.Cre). Moreover, we derived MC gene signatures from murine bone marrow-derived MC and used them to interrogate five human cohorts of LADC patients. Tumor-free cKitWsh and Cpa3.Cre mice were deficient in alveolar and skin KIT-dependent (KIT+) MC, but cKitWsh mice retained normal KIT-independent (KIT-) MC in the airways. Both KIT+ and KIT- MC infiltrated murine LADC to varying degrees, but KIT+ MC were more abundant and promoted LADC initiation and progression through interleukin-1β secretion. KIT+ MC and their transcriptional signature were significantly enriched in human LADC compared to adjacent normal tissue, especially in the subset of patients with KRAS mutations. Importantly, MC density increased with tumor stage and high overall expression of the KIT+ MC signature portended poor survival. Collectively, our results indicate that KIT+ MC foster LADC development and represent marked therapeutic targets.
AU  - Lilis, I.*
AU  - Ntaliarda, G.*
AU  - Papaleonidopoulos, V.*
AU  - Giotopoulou, G.A.*
AU  - Oplopoiou, M.*
AU  - Marazioti, A.*
AU  - Spella, M.*
AU  - Marwitz, S.*
AU  - Goldmann, T.*
AU  - Bravou, V.*
AU  - Giopanou, I.*
AU  - Stathopoulos, G.T.
C1  - 55870
C2  - 46646
CY  - 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
TI  - Interleukin-1β provided by KIT-competent mast cells is required for KRAS-mutant lung adenocarcinoma.
JO  - OncoImmunology
VL  - 8
IS  - 7
PB  - Taylor & Francis Inc
PY  - 2019
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - It is undeniably one of the greatest findings in biology that (with some very minor exceptions) every cell in the body possesses the whole genetic information needed to generate a complete individual. Today, this concept has been so thoroughly assimilated that we struggle to still see how surprising this finding actually was: all cellular phenotypes naturally occurring in one person are generated from genetic uniformity, and thus are per definition epigenetic. Transcriptional mechanisms are clearly critical for developing and protecting cell identities, because a mis-expression of few or even single genes can efficiently induce inappropriate cellular programmes. However, how transcriptional activities are molecularly controlled and which of the many known epigenomic features have causal roles remains unclear. Today, clarification of this issue is more pressing than ever because profiling efforts and epigenome-wide association studies (EWAS) continuously provide comprehensive datasets depicting epigenomic differences between tissues and disease states. In this commentary, we propagate the idea of a widespread follow-up use of epigenome editing technology in EWAS studies. This would enable them to address the questions of which features, where in the genome, and which circumstances are essential to shape development and trigger disease states.
AU  - Liu, T.*
AU  - Larionova, I.*
AU  - Litviakov, N.*
AU  - Riabov, V.*
AU  - Zavyalova, M.V.*
AU  - Tsyganov, M.*
AU  - Buldakov, M.*
AU  - Song, B.*
AU  - Moganti, K.*
AU  - Kazantseva, P.*
AU  - Slonimskaya, E.*
AU  - Kremmer, E.
AU  - Flatley, A.
AU  - Klüter, H.*
AU  - Cherdyntseva, N.V.*
AU  - Kzhyshkowska, J.*
C1  - 53281
C2  - 44746
CY  - 6-9 Carlton House Terrace, London Sw1y 5ag, England
TI  - Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy.
JO  - OncoImmunology
VL  - 7
IS  - 6
PB  - Royal Soc
PY  - 2018
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - The lungs are ubiquitous receptacles of metastases originating from various bodily tumors. Although osteopontin (SPP1) has been associated with tumor dissemination, the role of its isoforms in lung-directed metastasis is incompletely understood. We employed syngeneic mouse models of spontaneous and induced lung-targeted metastasis in C57BL/6 mice competent and deficient in both Spp1 alleles. Tumor-derived osteopontin expression was modulated using either stable anti-Spp1 RNA interference, or forced overexpression of intracellular and secreted Spp1 isoforms. Identified osteopontin's downstream partners were validated using lung adenocarcinoma cells conditionally lacking the Trp53 gene and Ccr2-deficient mice. We determined that host-derived osteopontin was dispensable for pulmonary colonization by different tumor types. Oppositely, tumor-originated intracellular osteopontin promoted tumor cell survival by preventing tumor-related protein 53-mediated apoptosis, while the secretory osteopontin functioned in a paracrine mode to accelerate lung metastasis by enhancing tumor-derived C-C-motif chemokine ligand 2 signaling to cognate host receptors. As new ways to target osteopontin signaling are becoming available, the cytokine may constitute an important therapeutic target against pulmonary involvement by cancers of other organs.
AU  - Giopanou, I.*
AU  - Lilis, I.*
AU  - Papaleonidopoulos, V.*
AU  - Agalioti, T.*
AU  - Kanellakis, N.I.*
AU  - Spiropoulou, N.*
AU  - Spella, M.*
AU  - Stathopoulos, G.T.
C1  - 50645
C2  - 42754
CY  - Philadelphia
TI  - Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis.
JO  - OncoImmunology
VL  - 6
IS  - 1
PB  - Taylor & Francis Inc
PY  - 2017
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - Immunotherapy is currently investigated as treatment option in many types of cancer. So far, results from clinical trials have demonstrated that significant benefit from immunomodulatory therapies is restricted to patients with select histologies. To broaden the potential use of these therapies, a deeper understanding for mechanisms of immunosuppression in patients with cancer is needed. Soft-tissue sarcoma (STS) presents a medical challenge with significant mortality even after multimodal treatment. We investigated function and immunophenotype of peripheral natural killer (NK) cells from chemotherapy-naive STS patients (1st line) and STS patients with progression or relapse after previous chemotherapeutic treatment (2nd line). We found NK cells from peripheral blood of both STS patient cohorts to be dysfunctional, being unable to lyse K562 target cells while NK cells from renal cell cancer (RCC) patients did not display attenuated lytic activity. Ex vivo stimulation of NK cells from STS patients with interleukin-2 plus TKD restored cytotoxic function. Furthermore, altered NK cell subset composition with reduced proportions of CD56dim cells could be demonstrated, increasing from 1st- to 2nd-line patients. 2nd-line patients additionally displayed significantly reduced expression of receptors (NKG2D), mediators (CD3ζ), and effectors (perforin) of NK cell activation. In these patients, we also detected fewer NK cells with CD57 expression, a marker for terminally differentiated cytotoxic NK cells. Our results elucidate mechanisms of NK cell dysfunction in STS patients with advanced disease. Markers like NKG2D, CD3ζ, and perforin are candidates to characterize NK cells with effective antitumor function for immunotherapeutic interventions.
AU  - Bücklein, V.L.
AU  - Adunka, T.*
AU  - Mendler, A.N.
AU  - Issels, R.D.*
AU  - Subklewe, M.
AU  - Schmollinger, J.C.*
AU  - Nößner, E.
C1  - 49064
C2  - 41667
CY  - Philadelphia
TI  - Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients.
JO  - OncoImmunology
VL  - 5
IS  - 7
PB  - Taylor & Francis Inc
PY  - 2016
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - The tumor microenvironment is composed of many immune cell subpopulations and is an important factor in the malignant progression of neoplasms, particularly breast cancer (BC). However, the cytokine networks that coordinate various regulatory events within the BC interstitium remain largely uncharacterized. Moreover, the data obtained regarding the origin of cytokine secretions, the levels of secretion associated with tumor development, and the possible clinical relevance of cytokines remain controversial. Therefore, we profiled 27 cytokines in 78 breast tumor interstitial fluid (TIF) samples, 43 normal interstitial fluid (NIF) samples, and 25 matched serum samples obtained from BC patients with Luminex xMAP multiplex technology. Eleven cytokines exhibited significantly higher levels in the TIF samples compared with the NIF samples: interleukin (IL)-7, IL-10, fibroblast growth factor-2, IL-13, interferon (IFN)γ-inducible protein (IP-10), IL-1 receptor antagonist (IL-1RA), platelet-derived growth factor (PDGF)-β, IL-1β, chemokine ligand 5 (RANTES), vascular endothelial growth factor, and IL-12. An immunohistochemical analysis further demonstrated that IL-1RA, IP-10, IL-10, PDGF-β, RANTES, and VEGF are widely expressed by both cancer cells and tumor-infiltrating lymphocytes (TILs), whereas IP-10 and RANTES were preferentially abundant in triple-negative breast cancers (TNBCs) compared to Luminal A subtype cancers. The latter observation corresponds with the high level of TILs in the TNBC samples. IL-1β, IL-7, IL-10, and PDGFβ also exhibited a correlation between the TIF samples and matched sera. In a survival analysis, high levels of IL-5, a hallmark TH2 cytokine, in the TIF samples were associated with a worse prognosis. These findings have important implications for BC immunotherapy research.
AU  - Espinoza, J.A.*
AU  - Jabeen, S.*
AU  - Batra, R.
AU  - Papaleo, E.*
AU  - Haakensen, V.*
AU  - Timmermans Wielenga, V.*
AU  - Talman, M.L.M.*
AU  - Brunner, N.*
AU  - Børresen-Dale, A.L.*
AU  - Gromov, P.*
AU  - Helland, Å.*
AU  - Kristensen, V.N.*
AU  - Gromova, I.*
C1  - 50220
C2  - 42111
CY  - Philadelphia
TI  - Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics.
JO  - OncoImmunology
VL  - 5
IS  - 12
PB  - Taylor & Francis Inc
PY  - 2016
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients' immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology, targetable tumor-associated antigens (TAA) are identified and exploited for engineered T-cell therapy. Here, the specific recognition and lytic potential of transgenic allo-restricted CD8(+) T cells, directed against the ES-associated antigen 6-transmembrane epithelial antigen of the prostate 1 (STEAP1), was examined. Following repetitive STEAP1(130) peptide-driven stimulations with HLA-A*02:01(+) dendritic cells (DC), allo-restricted HLA-A*02:01(-)CD8(+) T cells were sorted with HLA-A*02:01/peptide multimers and expanded by limiting dilution. After functional analysis of suitable T cell clones via ELISpot, flow cytometry and xCELLigence assay, T cell receptors' (TCR) alpha- and beta-chains were identified, cloned into retroviral vectors, codon optimized, transfected into HLA-A*02:01(-) primary T cell populations and tested again for specificity and lytic capacity in vitro and in a Rag2(-/-) gamma c(-/-) mouse model. Initially generated transgenic T cells specifically recognized STEAP1(130)-pulsed or transfected cells in the context of HLA-A*02:01 with minimal cross-reactivity as determined by specific interferon-g (IFN gamma) release, lysed cells and inhibited growth of HLA-A*02:01(+) ES lines more effectively than HLA-A*02:01(-) ES lines. In vivo tumor growth was inhibited more effectively with transgenic STEAP1(130)-specific T cells than with unspecific T cells. Our results identify TCRs capable of recognizing and inhibiting growth of STEAP1-expressing HLA-A*02:01(+) ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1-expressing tumors.
AU  - Schirmer, D.*
AU  - Gruenewald, T.G.P.*
AU  - Klar, R.*
AU  - Schmidt, O.*
AU  - Wohlleber, D.*
AU  - Rubio, R.A.*
AU  - Uckert, W.*
AU  - Thiel, U.*
AU  - Bohne, F.
AU  - Busch, D.H.*
AU  - Krackhardt, A.M.*
AU  - Burdach, S.*
AU  - Richter, G.H.S.*
C1  - 49164
C2  - 41685
CY  - Philadelphia
TI  - Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity.
JO  - OncoImmunology
VL  - 5
IS  - 6
PB  - Taylor & Francis Inc
PY  - 2016
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - Dendritic cells (DCs) essentially contribute to the induction and regulation of innate and adaptive immunity. Based on these important properties, DCs may profoundly influence tumor progression in patients. However, little is known about the role of distinct human DC subsets in primary tumors and their impact on clinical outcome. In the present study, we investigated the characteristics of human 6-sulfo LacNAc (slan) DCs in clear cell renal cell carcinoma (ccRCC). slanDCs have been shown to display various tumor-directed properties and to accumulate in tumor-draining lymph nodes from patients. When evaluating 263 ccRCC and 227 tumor-free tissue samples, we found increased frequencies of slanDCs in ccRCC tissues compared to tumor-free tissues. slanDCs were also detectable in the majority of 24 metastatic lymph nodes and 67 distant metastases from ccRCC patients. Remarkably, a higher density of slanDCs was significantly associated with a reduced progression-free, tumor-specific or overall survival of ccRCC patients. Tumor-infiltrating slanDCs displayed an immature phenotype expressing interleukin-10. ccRCC cells efficiently impaired slanDC-induced T-cell proliferation and programming as well as natural killer (NK) cell activation. In conclusion, these findings indicate that higher slanDC numbers in ccRCC tissues are associated with poor prognosis. The induction of a tolerogenic phenotype in slanDCs leading to an insufficient activation of innate and adaptive antitumor immunity may represent a novel immune escape mechanism of ccRCC. These observations may have implications for the design of therapeutic strategies that harness tumor-directed functional properties of DCs against ccRCC.
AU  - Toma, M.*
AU  - Wehner, R.*
AU  - Kloss, A.*
AU  - Huebner, L.*
AU  - Fodelianaki, G.*
AU  - Erdmann, K.*
AU  - Fuessel, S.*
AU  - Zastrow, S.*
AU  - Meinhardt, M.*
AU  - Seliger, B.*
AU  - Brech, D.
AU  - Nößner, E.
AU  - Tonn, T.*
AU  - Schaekel, K.*
AU  - Bornhaeuser, M.*
AU  - Bachmann, M.P.*
AU  - Wirth, M.P.*
AU  - Baretton, G.*
AU  - Schmitz, M.*
C1  - 45318
C2  - 37294
CY  - Philadelphia
TI  - Accumulation of tolerogenic human 6-sulfo LacNAc dendritic cells in renal cell carcinoma is associated with poor prognosis.
JO  - OncoImmunology
VL  - 4
IS  - 6
PB  - Taylor & Francis Inc
PY  - 2015
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - The clinical use of lymphocytes engineered to express high affinity T-cell receptors (TCRs) specific for two broadly expressed tumor-associated antigens is strongly limited by MHC-restricted fratricide of lymphocytes and TCR-mediated killing of hematopoietic stem cells. Specific clinical applications must therefore be conceived to bypass these limitations.
AU  - Schendel, D.J.
AU  - Frankenberger, B.
C1  - 24333
C2  - 31524
TI  - Limitations for TCR gene therapy by MHC-restricted fratricide and TCR-mediated hematopoietic stem cell toxicity.
JO  - OncoImmunology
VL  - 2
IS  - 1
PB  - Landes Bioscience
PY  - 2013
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - T cells expressing high avidity T-cell receptors (TCRs) have been shown to mediate superior therapeutic effects. A novel koff-rate assay allows for the quantitative and reproducible assessment of the avidity of TCRs for their ligands directly on living T cells, ex vivo. This assay might facilitate the selection of T cells with an optimal avidity for their target, hence favoring the development of adoptive immunotherapeutic regimens.
AU  - Weißbrich, B.*
AU  - Nauerth, M.*
AU  - Busch, D.H.
C1  - 28917
C2  - 33577
TI  - Adoptive immunotherapy: New assay for the identification of T cells with optimal avidity.
JO  - OncoImmunology
VL  - 2
IS  - 10
PB  - Landes Bioscience
PY  - 2013
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - Cytotoxic lymphocytes and dendritic cells infiltrating human renal cell carcinoma (RCC) are not sufficient to prevent tumor progression. Our studies identified alterations of the immune cell infiltrate as well as some of the underlying mechanisms. This knowledge should facilitate the development of anti-RCC therapies that achieve better tumor control.
AU  - Nößner, E.
AU  - Brech, D.
AU  - Mendler, A.N.
AU  - Masouris, I.
AU  - Schlenker, R.
AU  - Prinz, P.U.
C1  - 23938
C2  - 31296
SP  - 1451-1453
TI  - Intratumoral alterations of dendritic-cell differentiation and CD8+ T-cell energy are immune escape mechanisms of clear cell renal cell carcinoma.
JO  - OncoImmunology
VL  - 1
IS  - 8
PB  - Landes Bioscience
PY  - 2012
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - The adoptive transfer of lymphocytes expressing high-avidity T-cell receptors with antitumor specificity provides a promising therapy for cancer patients. Recently, we compared 12 HLA-A2-restricted, tyrosinase peptide-specific CD8+ cytotoxic T-lymphocyte (CTL) clones and demonstrated that polyfunctional type 1 helper (Th1)-cytokine secretion serves to rapidly select high-quality, high-avidity CTLs.
AU  - Wilde, S.
AU  - Schendel, D.J.
C1  - 11078
C2  - 30499
SP  - 1643-1644
TI  - High-quality and high-avidity T cell clones specific for tumor-associated antigens and how to find them.
JO  - OncoImmunology
VL  - 1
IS  - 9
PB  - Landes Bioscience
PY  - 2012
SN  - 2162-4011
ER  - 

TY  - JOUR
AB  - Designer T cells expressing transgenic T cell receptors (TCR) with anti-tumor specificity offer new treatment options for cancer patients. We developed a three phase procedure to identify T cells of high avidity based on the fact that T cells recognizing peptides presented by allogeneic MHC efficiently kill tumor cells. Autologous dendritic cells (DC) are co-transfected with ivt-RNA encoding an allogeneic MHC molecule and a selected antigen to allow them to express allogeneic MHC-peptide complexes that activate allo-restricted peptide-specific T cells. This approach provides great flexibility for obtaining high-avidity T cells as potential sources of TCR for adoptive T cell therapy.
AU  - Wilde, S.
AU  - Geiger, C.
AU  - Milosevic, S.
AU  - Mosetter, B.
AU  - Eichenlaub, S.
AU  - Schendel, D.J.
C1  - 11178
C2  - 30536
SP  - 129-140
TI  - Generation of allo-restricted peptide-specific T cells using RNA-pulsed dendritic cells: A three phase experimental procedure.
JO  - OncoImmunology
VL  - 1
IS  - 2
PB  - Landes Bioscience
PY  - 2012
SN  - 2162-4011
ER  -