A case series in patients with enteropathy and granulomatous diseases

Background Although sarcoidosis and celiac disease are both chronic immunologic disorders involving multiple organ systems, reports about association of diseases in individual patients are sparse. While sarcoidosis is a chronic granulomatous disease presumably reflecting an exaggerated response to an unknown antigen, celiac disease is a T cell-driven disease triggered by ingestion of gluten, a protein composite found in wheat and related grains. Case presentation We present three cases with a longstanding history of sarcoidosis that have been additionally diagnosed with celiac-like enteropathy. In two cases, celiac disease was established applying celiac- specific serology and duodenal histology, while one case was revealed as an AIE-75-positive autoimmune enteropathy. The HLA-DR3/DQ2 haplotype was confirmed in both celiac patients, hence confirming previous data of linkage disequilibrium as a cause for disease association. Remarkably, one celiac patient presented with granulomatous nodulae in the ileum, thus reflecting an intestinal sarcoid manifestation. In contrast the patient with an autoimmune enteropathy, was HLA-DQ9/DQ6-positive, also arguing against CD. Conclusions Associations of sarcoidosis and celiac disease are rare but do occur. Determining the HLA status in patients with complex autoimmune associations might help classifying involved disease entities

Prognostic Significance of Estrogen Receptor Alpha in Oral Squamous Cell Carcinoma

Simple Summary: Although the survival rate has improved over the past decades, the prognosis of oral squamous cell carcinoma (OSCC) is still poor, and new treatment strategies are required. The aim of this study was to evaluate estrogen receptor alpha (ERa) expression in OSCC in a large patient cohort as a potential prognostic marker and therapeutic target. The findings indicated a rare expression of ERa that, however, was associated with a dramatic decrease of overall survival in male patients. In ERα-positive OSCC patients, an ER-based therapeutic (adjuvant) approach in the future might be conceivable based on the findings of this study. Abstract: Introduction: Several studies suggest an estrogen receptor alpha (ERα)-mediated influence on the pathogenesis of oral squamous cell carcinoma (OSCC), as described for other malignancies that are not considered to be primarily hormone-dependent. Recently, an association between ERα expression and improved survival in oropharyngeal squamous cell carcinoma (OPSCC) has been found. However, the prognostic relevance of ERα in OSCC has not been proven to date. Therefore, the aim of this study was to evaluate ERα expression in OSCC in a large patient cohort and analyze its influence on survival and recurrence. Material and methods: A total of 316 patients with primary OSCC who received initial surgical therapy were included in this analysis. The expression of ERα was evaluated on tissue microarrays by immunohistochemistry in the primary tumor and/or primary lymph node metastases. The expression level was quantified by light microscopy using the immunoreactive score (IRS) for estrogen receptor detection. An IRS equal to or greater than 2 was considered positive. The 5-year overall survival (OS) and relapse-free survival (RFS) were examined by the Kaplan-Meier method and log-rank test. Results: A total of 316 patients (111 females; 205 males) with a mean age of 61.3 years (range 27-96 years) were included in this study. In 16 patients (5.1%; 6 females and 10 males), positive ERα expression was found in the primary tumor (n = 11; 11/302) or lymph node metastases (n = 5; 5/52). Patients with positive ERα expression in primary tumors/primary lymph node metastases had a significantly lower OS and RFS (p = 0.012; p = 0.0053) compared to ERα-negative patients. Sub-group analysis in relation to gender revealed a highly significant influence of ERα expression on OS and RFS in males but not in females, both for the ERα-positive primary tumor cohort (males: p = 0.0013; p < 0.0001; females: p = 0.56; p = 0.89) and the ERα-positive primary tumor/primary lymph node metastasis cohort (males: p < 0.0001; p < 0.0001; females: p = 0.95; p = 0.96). In multivariate cox regression analysis, the ERα IRS of primary tumors (dichotomized; ERα+ vs. ERα-) was an independent risk factor for OS (HR = 4.230; 95%CI 1.616-11.076; p = 0.003) and RFS (HR = 12.390; 95%CI 4.073-37.693; p < 0.001) in the male cohort. There was a significant difference (p = 0.006) of ERα positivity with regard to the localization of the primary tumor. ERα positivity in the primary tumor was significantly associated (p = 0.026) with UICC stage, with most of the cases being diagnosed in stage IV. Furthermore, there was a significantly (p = 0.049) higher rate of bone infiltration in ERα-positive patients. Conclusion: Expression of ERα is rare in OSCC; however, it is associated with a dramatic decrease in OS in male patients. Further studies are necessary to confirm our results and to evaluate the exact mechanism underlying this observation. Hence, ERα-positive OSCC patients might benefit from an ER-based therapeutic (adjuvant) approach in the future

Prognosis of patients with malignant mesothelioma by expression of programmed cell death 1 ligand 1 and mesothelin in a contemporary cohort in Finland

ObjectivesWe aimed to describe mesothelin (MSLN) and programmed cell death 1 ligand 1 (PD-L1) tumour overexpression amongst patients with malignant mesothelioma (MM), and their associations with survival, amongst a cohort of patients with MM in Finland.MethodsBetween 2004 and 2017, 91 adults with histologically confirmed MM were identified from the Auria Biobank in Finland and followed-up using linked data from electronic health records and national statistics. Biomarker content in tumour cell membranes was determined using automated Immunohistochemistry on histological sections. Stained tumour sections were scored for MSLN and PD-L1 intensity. Adjusted associations between MSLN/PD-L1 co-expression and mortality were evaluated by estimating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression.ResultsBiomarker overexpression occurred in 52 patients for MSLN and 34 patients for PD-L1 and was associated with tumour histology and certain comorbidities. Fifteen per cent of patients had a tumour that overexpressed both biomarkers; r =-0.244, p-value: 0.02. Compared with MSLN+/PD-L1+ patients, HRs (95% CIs) for death were 4.18 (1.71–10.23) for MSLN-/PD-L1+ patients, 3.03 (1.35–6.77) for MSLN-/PD-L1- patients, and 2.13 (0.97–4.67) for MSLN+/PD-L1- patients.ConclusionsBoth MSLN and PD-L1 markers were independent prognostic indicators in patients with MM. Overexpression of MSLN was associated with longer survival; yet their combined expression gave a better indication of survival. The risk of death was four times higher amongst MSLN-/PD-L1+ patients than in MSLN+/PD-L1+ patients.</p

Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)

SIMPLE SUMMARY: Anaplastic large cell lymphoma (ALCL) is a lymphoid malignancy considered to be derived from T cells. Currently, two types of systemic ALCL are distinguished: anaplastic lymphoma kinase (ALK)-positive and ALK-negative ALCL. Although ALK(+) and ALK(−) ALCL differ at the genomic and molecular levels, various key biological and molecular features are highly similar between both entities. We have developed the concept that both ALCL entities share a common principle of pathogenesis. In support of this concept, we here describe a common deregulation of CD74, which is usually not expressed in T cells, in ALCL. Ligation of CD74 induces cell death of ALCL cells in various conditions, and an anti-CD74-directed antibody-drug conjugate efficiently kills ALCL cell lines. Furthermore, we reveal expression of the proto-oncogene and known CD74 interaction partner MET in a fraction of ALCL cases. These data give insights into ALCL pathogenesis and might help to develop new treatment strategies for ALCL. ABSTRACT: In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK(+)) ALCL. Key pathogenic events in ALK-negative (ALK(−)) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK(+) and ALK(−) ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK(+) ALCL or of CD95 death-receptor signaling in ALK(−) ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity

The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.

Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK- anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK+ ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17-, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3

Morphological and functional investigations on the role of the T-bet transcription factor in infectious lymphadenopathies, autoimmune diseases and malignant lymphomas

Die Bildung einer effizienten Immunantwort ist für das individuelle Überleben essentiell. Das Zusammenspiel der angeborenen und erworbenen Immunantwort nimmt dabei eine besondere Stellung ein. Die Effizienz der jeweiligen Immunantwort beruht dabei nicht nur auf dem optimalen zeitlichen Ablauf, sondern auch auf dem Interagieren der unterschiedlichen Zelltypen. Für den reibungslosen Ablauf sind unter Anderem sog. Master-Regulatoren verantwortlich, die wesentlich die Bildung der Immunmodulation beeinflussen. Sind sie in ihrer Funktion beeinträchtigt, resultieren schwere häufig mit dem Leben nicht vereinbare Krankheitsbilder. Während die B-Zellen in erster Linie durch die Antikörperproduktion zu einer gerichteten Immunantwort beitragen, bilden die T-Zellen unterschiedliche Helferzellen aus. Die naiven T-Helfer- Zellen können in Abhängigkeit des Erregers zu Th1, Th2, Treg und Th17 Zellen differenzieren. Dabei wird die Th1-Antwort im Wesentlichen durch T-box- expressed in T-cells (T-bet)gebildet. T-bet ist der Masterregulator der Th1-Antwort, d.h. es wird hauptsächlich durch dieses Molekül die Th1-Antwort angeschoben. T-bet ist für die Differenzierung der Th0 Zelle in Richtung Th1 Zelle verantwortlich. Dabei blockiert es zusätzlich die Differenzierung in Th2 Zellen. Aber hierin besteht nicht die einzige Funktion von T-bet. Funktionelle Untersuchungen in-vitro und an Tiermodellen konnten aufdecken, dass T-bet zusätzlich auch eine wichtige Rolle in der Gestaltung der T-Zell-unabhängigen Immunantwort über die Beeinflussung des IgG Klassenwechsels der B-Zellen und in der Bildung der Th17-Antwort spielt. Letzteres spricht dafür, dass T-bet offenbar in der Pathogenese von Autoimmunerkrankungen eine wesentliche Bedeutung hat. Nachdem die meisten Untersuchungen dazu in-vitro oder an Tiermodellen erfolgten, galt es nun, diese Ergebnisse auf das Primärgewebe zu übertragen. Dabei haben wir zunächst Krankheiten untersucht, die auf einer Th1-Antwort beruhen. Im Falle der Sprue/Zöliakie konnte dabei durch Doppelmarkierungen gezeigt werden, dass die CD8+ intraepithelialen Lymphozyten offenbar im Sinne einer Umgebungsreaktion die Th1-Antwort mit unterstützen. Bei Erkrankungen, bedingt durch intrazelluläre Erreger, wie der durch Toxoplasmen verursachten Piringer-Lymph¬adenitis oder der Epstein-Barr Virus- Infektion, beobachteten wir hingegen das zusätzliche Vorhandensein von B-Zellen, die T-bet exprimieren und sich an der Th1-Antwort beteiligen. Dabei fiel auf, dass eine besondere B-Zell Population, die monozytoiden B-Zellen, eine kräftige T-bet Expression zeigten. Bezüglich der Piringer-Lymphadenitis konnte zudem eine Interferon-gamma Expression der monozytoiden B-Zellen und eine IL-2 Minderexpression der T-Zellen nachgewiesen werden. Dies gab zu der Hypothese Anlass, dass die B-Zellen versuchen, die Aufgabe ineffizienter T-Zellen zu ersetzen. In einer vergleichenden Studie zwischen der Sprue/Zöliakie und der lymphozytären Kolitis konnten wir zudem zeigen, dass bei der Sprue eine reine Th1-Antwort vorliegt, während die lymphozytäre Kolitis offenbar eine kombinierte Th1- und Th2-Antwort aufweist. Da sich in eigenen Vorarbeiten und in denen anderer Arbeitsgruppen herauskristallisierte, dass T-bet auch in B- und T-Zell-Lymphomen von den Tumorzellen exprimiert wird, erfolgten auch weitere immunhistologische und funktionelle Studien an einer Vielzahl von humanen malignen Lymphomen. Im Falle der Haarzell-Leukämie (HCL) konnten wir herausarbeiten, dass die Tumorzellen nicht nur sehr intensiv T-bet exprimieren, sondern auch Interferon-gamma. Während die T bet Darstellung sich als ein hilfreiches und empfindliches Werkzeug für die histologische Diagnositk der Haarzellleukämie herausstellte, könnte der Interferon-gamma Nachweis im Serum als klinischer Verlaufsparameter genutzt werden. Die Untersuchungen am angioimmunoblastischen T-Zell-Lymphom (AITCL) führten zur Identifizierung unterschiedlicher T-bet Expressionsmuster der in diesem Lymphom vorkommenden nicht neoplastichen B- und neoplastischen T Zellen. Die räumliche Assoziation der T-bet exprimierenden B-Zellen mit den hohen endothelialen Venolen und die Tatsache, dass die neoplastischen T Zellen neben T-bet auch VEGF alpha und CXCL13 exprimieren, legt den Schluss nahe, dass in diesem besonderen Umfeld zusätzlich eine Th17-Antwort gebildet wird, was die charakteristischen klinischen Symptome dieses Lymphoms erklären würde.Mounting of an adequate immune response is essential for the individual survival. The interaction between native and adaptive immune response is the key point in this proposal. The efficiency of each immune response is based not only on the optimal time flow but also on the interaction of the different cell types. Master regulators for the different cell types are fundamental in influencing the immune modulation. If they are affected in function severe disease or death are the results. B-cells contribute to a specific immune response through antibody production, while the T-cells generate different helper cells. Different microorganisms can lead to a differentiation of naïve T-cells into one of the four known subsets Th1, Th2, Treg and Th17. The development of a Th1 immune response is mainly initiated by its master regulator molecule T.box-expressed in T-cells (T-bet). T-bet is responsible for the differentiation of a Th0 cell into a Th1 cell while it additionally inhibits the differentiation into a Th2 cell. The spectrum of T-bet functions is however not limited in the Th1 response initiation and priming. Functional in-vitro as well as in-vivo investigations have revealed that T-bet plays a key role in shaping the T-cell independent immune response through its influence on the IgG class switch and the generation of the Th17-response. The latter finding implicates the relevance of T-bet in the pathogenesis of autoimmune diseases. As most of this data had been generated either in-vitro or using animal experiments our goal has been to validate them in human tissue and its diseases. Therefore, we have concentrated on diseases where a Th1-immune response is involved in their pathogenesis. In celiac disease we could show by means of double immunolabellings that the intraepithelial CD8-positive T-cells express T-bet and thus apparently support a Th1 immune response. Our investigation of various lymphadenopathies caused by intracellular infectious agents like Toxoplasma gondii or Epstein-Barr virus led to the finding that in addition to T-cells several B-cells do also express T-bet and thus participate at the Th1 response. During these investigations we observed that a particular B-cell subset, the monocytoid B-cells, constantly showed an intense T-bet expression. Further studies could show that the monocytoid B-cells occurring in lymphadenitis caused by Toxoplasma gondii express interferon gamma, while the T-cells underexpressed interleukin-2. This led to the hypothesis that the B-cells are trying to overcome and compensate the temporal inefficiency of the T-cells. In an additional comparative study of celiac disease and lymphocytic colitis we could show that while celiac disease is characterized by a pure Th1 immune response whereas in lymphocytic colitis a combined Th1 and Th2 response does occur. As we and other groups could show that T-bet expression is also present in malignant lymphomas of the T- and B-cell lineage we expanded our immunohistochemical and functional studies in this field. This led to the findings that hairy cell leukaemia is characterized not only by an intense T-bet expression but also by an interferon-gamma production by the neoplastic cells. We could also show that the intense T-bet expression by the hairy cell leukaemia cells is helpful for the correct diagnosis and the identification of minimal bone marrow infiltrates and that the measurement of interferon gamma serum levels can be helpful in monitoring the disease activity. Our immunohistological investigations of angioimmunoblastic T-cell lymphoma cases revealed a spectrum of different T-bet expression patterns in the neoplastic T-cells and the non- neoplastic B-cells present in this lymphoma. The topography of the T-bet expressing B-cells arranged in the vicinity of high endothelial venules and the fact that the neoplastic T-cells express not only T-bet but also CXCL13 and VEGF-alpha led to the concept of a Th-17 permissive microenvironment responsible for the peculiar clinical picture of this lymphoma

The Challenge to the Pathologist of PD-L1 Expression in Tumor Cells of Non-Small-Cell Lung Cancer&mdash;An Overview

In recent years, the treatment of non-small-cell lung cancer (NSCLC) has been fundamentally changed by immunotherapy where the immune system is reactivated using anti-programmed cell death protein 1/programmed death ligand 1 (PD1/PD-L1) checkpoint inhibition. With this, the immunohistological detection of PD-L1 has become one of the most important predictive biomarkers, leading pathologists to play a central role in the immuno-oncological therapy decisions. This has brought them the challenge of requiring the knowledge of relevant checkpoint inhibitors (CI), different PD-L1 scores and cut-offs as well as the choice of the right tissues and controls. Their involvement is also required in the careful validation of both clinical trial assays (CTAs) and laboratory developed tests (LDTs), in addition to the internal and external quality assessment and the interpretation and scoring of the staining based on specialist training. After the training of tumor proportion score (TPS) scoring in NSCLC, pathologists show a high level of concordance, with some variation between different cut-offs. Since not all patients benefit from immunotherapy, further research is needed to validate new predictive markers and optimize existing ones. In this context, these studies focus on a combination of PD-L1 and molecular signatures

Favorable therapeutic response after anti-Mesothelin antibody–drug conjugate treatment requires high expression of Mesothelin in tumor cells

Purpose The cell surface glycoprotein Mesothelin is overexpressed in ovarian, fallopian tube, endometrial, cervical and primary peritoneal cancer and, therefore, might become a particular interesting tumor target in gynecologic oncology. However, even in malignant tumors of the same entity the level of Mesothelin expression varies between individuals, hence it can be expected that the response to Mesothelin-targeting therapies will be variable as well. In this study we explored the therapeutic potency of a novel anti-Mesothelin antibody–drug conjugate (Anetumab ravtansine) as a function of Mesothelin expression in the targeted tumor cells. Methods Anti-tumor activity studies were performed in human uterine xenograft tumor models that express Mesothelin at high, moderate or low levels. The antibody–drug conjugate (ADC) was applied in varying doses ranging from 2 to 15 mg/kg at variable intervals in tumor bearing SCID/beige mice and the impact on tumor growth was monitored. Results The therapeutic response to the anti-Mesothelin ADC correlated closely with the level of Mesothelin expression in tumor cells. Within the applied dose levels complete tumor regression was achieved only in tumors which expressed Mesothelin at particularly high levels (Hela cell tumors). The application of high anti-Mesothelin ADC doses less frequently was more efficious than giving lower doses at a higher frequency. Conclusion The studies confirm the great therapeutic potential of Anetumab ravtansine. However, a favorable treatment outcome requires strong Mesothelin expression in tumor cells. Future clinical trials may benefit from a more rigorous selection of appropriate patients based on the level of Mesothelin expression in their tumor tissue. If, in addition, it is possible to better control side effects by introducing protective measures and by doing so to increase the maximum tolerated dose, Anetumab ravtansine has the potency to become a valuable therapeutic tool, especially in the field of gynecological oncology

Prognostic impact of the post-treatment T cell composition and spatial organization in soft tissue sarcoma patients treated with neoadjuvant hyperthermic radio(chemo)therapy

Soft tissue sarcomas (STS) form a heterogeneous group of tumors sharing a mesenchymal origin. Despite good local control of the disease, the occurrence of distant metastases often limits survival of STS patients with localized, high-risk tumors of the extremities. Accumulating evidence suggests a central role for the tumor immune microenvironment in determining the clinical outcome and response to therapy. Thus, it has been reported that STS patients with a high immune signature and especially presence of B cells and tertiary lymphoid structures display improved overall survival and response to checkpoint inhibitor treatment. Here, we explored the effect of curative multimodal therapy on the T cell landscape of STS using multiplex immunohistochemistry. We analyzed the phenotype, frequency, and spatial distribution of STS-infiltrating CD8+ T cells by staining for CD8, 4-1BB, Granzyme B, Ki67, PD-1, and LAG-3 as well as CD3+ T helper cells using a panel consisting of CD3, T-bet, GATA3, RORγT, FoxP3, and Ki67. All patients received neoadjuvant radiotherapy plus locoregional hyperthermia with or without chemotherapy. While the treatment-naïve biopsy sample allows an analysis of baseline T cell infiltration levels, both intra- and peritumoral areas of the matched resected tissue were analyzed to assess composition and spatial distribution of the T cell compartment and its therapeutic modulation. Generally, post-treatment tissues displayed lower frequencies of CD3+ and CD8+ T cells. Association with clinical data revealed that higher post-treatment frequencies of peritumoral and intratumoral CD3+ T cells and intratumoral PD-1+ CD8+ T cells were significantly associated with improved disease-free survival (DFS), while these densities had no prognostic significance in the biopsy. Upon spatial analysis, a high ratio of intratumoral to peritumoral CD8+ T cells emerged as an independent prognostic marker for longer DFS. These results indicate that the STS T cell landscape is altered by multimodal therapy and may influence the clinical outcome of patients. An enhanced understanding of the STS immune architecture and its modulation by neoadjuvant therapy may pave the way towards novel treatment modalities and improve the long-term clinical outcome of STS patients