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There is evidence from studies on fibrotic diseases that a TH2 polarized immune response, characterized by the production of cytokines like IL-4, IL-5, and IL-13 is important for fibrosis development. Data concerning the role of TH2 polarized immune response for fibrogenesis in lymphomas are scarce. Using immunohistochemistry, we investigated paraffin embedded tissue specimens of 58 follicular lymphomas (FL) grade 1/2 with and without fibrosis. In FL with fibrosis, we detected more interfollicular GATA-3 positive lymphocytes and a shift towards a TH2 immune response. In areas of fibrosis, which were enriched with myofibroblasts, we observed a polarization of macrophages towards a M2 phenotype with expression of CD163. Our results hold some evidence that a polarization of the adaptive immune system towards a TH2 immune response in the tumor microenvironment is associated with increased fibrosis, which may indicate its functional relevance for either development or maintenance of fibrosis in FL. [ABSTRACT FROM PUBLISHER]

We investigated 41 diffuse large B-cell lymphomas (DLBCL) diagnosed at one center harboring ≥50% of latently Epstein–Barr virus (EBV)-infected neoplastic cells occurring in 34 patients aged ≥50 years and in 7 patients younger than 50 years in the absence of any known immunodeficiency for the expression patterns of EBV latent and immediate-early proteins, for the differentiation stage of the neoplastic cells, the presence of cytogenetic alterations and a possible co-infection with the human herpes virus (HHV)-8. Here, we show that EBV-positive DLBCLs rarely arise from naïve and more frequently from post-germinal center B-cells that often contain crippling immunoglobulin gene mutations. Most of the lymphomas did not exhibit breaks in theBCL2,BCL6, andMYCgenes and none of the cases investigated contained HHV-8 sequences. Patients aged <50 years performed better than older ones while in patients aged ≥50 years only the cellular composition had an impact on overall survival. [ABSTRACT FROM AUTHOR]

The presence of tumor cells with monocytoid morphology in marginal zone lymphoma (MZL) has been described previously. Reactive monocytoid B cells bear a distinct immunophenotype and typically express T-bet, which clearly distinguishes them from nodal marginal zone B cells. The latter are positive for CD27 and negative for T-bet. We analyzed 74 MZLs for the expression of T-bet and correlated these results with the presence of monocytoid morphology. Expression of T-bet correlated with the presence of monocytoid morphology in MZLs. In analogy to reactive monocytoid B lymphocytes, we also found a significantly lower relative amount of intratumoral T lymphocytes in extranodal MZL with monocytoid morphology. [ABSTRACT FROM AUTHOR]

Angioimmunoblastic T-cell lymphoma (AITL) exhibits a multifaceted clinical picture and distinct architectural patterns that correlate with disease progression and the number of neoplastic cells. In this study we investigated the expression of the transcription factor T-bet and correlated it with the architectural patterns in 29 cases of AITL. Double immunolabelings for T-bet, CD20, CD3 or PD1 revealed the following patterns: predominant T-bet expression by neoplastic T-cells (A), by aggregates of small B-cells (B) or by B-immunoblasts (C). The majority of cases of AITL pattern II showed a T-bet expression pattern B (6/8 cases), while the majority of those with pattern III exhibited the T-bet pattern A (11/21 cases). We propose that T-bet expression by B-cells represents a T-cell independent immune response trying to cope with opportunistic infections, while T-bet expression by neoplastic T-cells is linked to the introduction of a Th17 response responsible for the immunologic derangements characteristic of AITL. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is an uncommon B-cell malignancy with unknown pathogenesis. In an earlier study, we demonstrated that HCL cells highly express the transcription factor T-box-expressed-in-T-cells (T-bet). T-bet is the master regulator of the T-helper (Th)1 cell response regulating interferon gamma (IFN-γ) production and also plays a central role in the T-cell independent Th1-like B-cell response. Here, we demonstrate by fluorescence activated cell sorting (FACS) analysis that neoplastic cells from the peripheral blood of five patients with HCL showed an enhanced expression of IFN-γ after stimulation. Additionally, a comparison with 55 healthy individuals revealed a significant elevation of IFN-γ in the sera of patients with HCL. Based on our recent findings that a non-neoplastic B-cell subset, the monocytoid B-cells, are T-bet positive and produce IFN-γ, we propose that monocytoid and hairy B-cells have a similar function and that the T-bet-IFN-γ axis is involved in the pathogenesis of HCL. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in which the authors talk about gene expression of Epstein-Barr virus (EBV) encoded proteins in angioimmunoblastic T-cell lymphoma and propose that T-cell lymphoma patients should be screened for serological signs of lytic reactivation and EBV viral load.

Background: Intra-tumoral CD8 + T-cell infiltration in squamous cell carcinoma of the head and neck (HNSCC) has previously been linked to the efficacy of cisplatin-based chemoradiation (CDDP-CRTX) and immune checkpoint inhibitor (ICI) monotherapy. Further detailed characterization of the tumor immune-micromilieu and its influence on outcome may guide the development of CRTX-ICI combinations. Methods: Comprehensive immune transcriptome analysis was applied to a training set of tumor specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients treated with CDDP-CRTX in the ARO-0401 phase III study (n = 33). A composite immune signature risk score (ISRS) for survival prediction was developed, and subsequently validated in two independent OPSCC cohorts treated with either CDDP-CRTX (n = 36) or mitomycin-based CRTX (MMC-CRTX, n = 31). Further validation of the ISRS was performed in the OPSCC subset (n = 79) of the TCGA HNSCC cohort. Potential interference between immune signatures and HPV status was evaluated in multivariate Cox regression models. Results: Significant differences according to the 3-y OS status in the abundance of tumor-infiltrating T- and B-cells, and the expression levels of 51 immune-related genes were observed. A risk score based on 13 differentially expressed genes involved in cytokine signaling, T-cell effector functions and the TNFR pathway was established as robust predictive factor of OS. Its predictive power was superior to the 6-gene interferon-gamma signature of ICI efficacy and independent of the HPV status. Conclusions: This study further elucidates the complex interaction of the tumor immune microenvironment with the efficacy of CDDP-CRTX in OPSCC. The results suggest immune markers for selection of patients treated with CRTX-ICI combinations. [ABSTRACT FROM AUTHOR]

Soft-tissue sarcomas (STS) are rare malignancies that account for 1% of adult cancers and comprise more than 50 entities. Current therapeutic options for advanced-stage STS are limited. Immune checkpoint inhibitors targeting the PD-1/PD-L1 signaling axis are being explored as new treatment modality in STS; however, the determinants of response to these agents are largely unknown. Using the sarcoma data set of The Cancer Genome Altas (TCGA) and an independent cohort of untreated high-grade STS, we analyzed DNA copy number status and mRNA expression ofPD-L1in a total of 335 STS cases. Copy number gains (CNG) were detected in 54 TCGA cases (21.1%), of which 21 (8.2%) harbored focalPD-L1CNG and that were most prevalent in myxofibrosarcoma (35%) and undifferentiated pleomorphic sarcoma (34%). In the untreated high-grade STS cohort, we detected CNG in six cases (7.6%). Analysis of co-amplified genes identified a 5.6-Mb core region comprising 27 genes, includingJAK2. Patients withPD-L1CNG had higherPD-L1expression compared with STS without CNG (fold change, 1.8;p= 0.02), an effect that was most pronounced in the setting of focalPD-L1CNG (fold change, 3.0;p= 0.0027). STS withPD-L1CNG showed a significantly higher mutational load compared with tumors with a diploidPD-L1locus (median number of mutated genes; 58 vs. 40;p= 3.6E-06), andPD-L1CNG were associated with inferior survival (HR = 1.82;p= 0.025). In contrast, T-cell infiltrates quantified by mRNA expression ofCD3Zwere associated with improved survival (HR = 0.88;p= 0.024) and consequently influenced the prognostic power ofPD-L1CNG, with lowCD3Zlevels conferring poor survival in cases withPD-L1CNG (HR = 1.8;p= 0.049). These data demonstrate thatPD-L1GNG and elevated expression ofPD-L1occur in a substantial proportion of STS, have prognostic impact that is modulated by T-cell infiltrates, and thus warrant investigation as response predictors for immune checkpoint inhibition. [ABSTRACT FROM AUTHOR]