An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression.

Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity

FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

乳がんの再発を起こす原因細胞を解明. 京都大学プレスリリース. 2023-11-16.The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na⁺/K⁺ pump. Accordingly, FXYD3⁺ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3⁺ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3⁺ CSCs were sensitive to senolytic Na⁺/K⁺ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3⁺ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na⁺/K⁺ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis

Basic and translational studies of follicular thyroid neoplasia

Thyroid tumors occur frequently in the general population and although the majority represents benign follicular adenomas (FTA), thyroid cancer constitutes 1% of all malignancies worldwide. Among the differentiated cancers, three main types are recognized, including the papillary and follicular forms (PTC and FTC) that originate from the follicular thyrocytes, and the medullary carcinoma that arises from the C-cells. The undifferentiated form, i.e. anaplastic carcinoma (ATC), is a highly aggressive cancer of sometimes unknown cellular origin. The overall goal of this thesis was to investigate the alternative genetic pathways leading to follicular thyroid tumorigenesis and thereby identify clinically relevant biomarkers. A large panel of primary non-medullary thyroid tumors of different histopathological diagnoses as well as human thyroid cell lines were analyzed. In Paper I, cytogenetic analyses of primary thyroid tumors and of the established thyroid cancer cell lines DRO, ARO and CGTH W- 1 were performed. Five of the 16 primary tumors revealed an abnormal karyotype including a FTC with a somatic translocation involving chromosomes 2, 5 and 10 and a PTC with a balanced translocation t(3;15). In Paper II, a panel of 87 follicular thyroid tumors was screened for the presence of PAX8PPARgamma chromosomal translocation. Interphase fluorescence in situ hybridization (iFISH), RTPCR followed by sequencing and Western blotting were used for the detection of the PAX8PPARgamma fusion on the DNA, RNA and protein level, respectively. The rearrangement was detected in 10 of 34 (29%) FTCs and in one of 20 (5%) atypical FTAs, but not in any of the 20 regular FTAs or 13 ATCs studied. The findings suggest that PAX8-PPARgamma occurs frequently in FTC and is highly suggestive of a malignant tumor. Subsequently, the functional consequences of PAX8-PPARgamma were explored (Paper III). Using highdensity oligonucleotide arrays, the gene expression profiles of FTCs bearing a PAX8-PPARgamma fusion were compared with FTCs lacking this fusion. Unsupervised clustering and multidimensional scaling analyses showed that PAX8-PPARgamma positive FTCs have a highly uniform and distinct gene expression signature and are likely to constitute a distinct biological entity. Notably, a large number of ribosomal protein and translation-associated genes were concurrently under-expressed in the FTCs with the fusion. In Paper IV, the role of Ras and its pro-apoptotic effectors NORE1A and RASSF1A in FTC development was investigated. Dramatically reduced mRNA expression of NORE1A was evident in all PAX8-PPARgamma positive FTCs, while RAS mutations and PAX8-PPARgamma fusion were mutually exclusive events. RASSF1A expression was reduced in the majority of the FTCs analyzed. In Paper V, expression of the PTEN tumor suppressor gene was analyzed in 87 sporadic thyroid tumors. Complete loss of PTEN mRNA expression was evident in six of the tumors and the transcriptional silencing of PTEN was significantly associated with the anaplastic subtype. No association was observed between the expression, loss of heterozygosity, and mutation status of PTEN in the 3 3 cases in which these parameters were compared. In Paper VI, 26 potential markers of malignancy were evaluated in 75 follicular thyroid tumors by TaqMan quantitative RT-PCR. A combination of five genes (TERT, TFF3, PPARgamma, EGR2 and CITED1) could accurately predict aggressive FTC, while two genes (TERT and TFF3) specifically detected malignant tumors

The interplay between eosinophils and T cells in breast cancer immunotherapy

Treatment with immune checkpoint inhibitors (ICI) has revolutionized cancer management for multiple tumor types, including breast cancer. However, not all patients respond to ICI, and unraveling the determinants and mechanisms of response still remains an unmet need. A recent study has uncovered the critical role of eosinophils in mediating immunotherapy effect in breast cancer, mainly by stimulating the activation of CD8+ T‐cells. Furthermore, the intratumoral eosinophil recruitment was directed by CD4+ T cells and the interleukins IL‐5 and IL‐33, thus providing the rationale for targeting eosinophils to enhance ICI response

Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy

Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor − host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed

A retrospective safety and efficacy analysis of the first patients treated with eribulin for metastatic breast cancer in Stockholm, Sweden

<div><p></p><p><b>Backgrounds.</b> Eribulin is a non-taxane, microtubule dynamics inhibitor approved for the treatment of patients with metastatic breast cancer (MBC) in Europe in March 2011.</p><p><b>Material and methods.</b> For the purpose of an internal quality control, all patients with MBC treated with eribulin at Karolinska University Hospital were registered in a database. Clinical data were collected retrospectively for patients that were registered by August 2012 and safety and efficacy of eribulin were evaluated. Treatment toxicity including fatigue, neurotoxicity and infection was graded according to CTCAE v4.0. Objective response to treatment was investigated using routinely performed radiological assessments. When only clinical assessments were made, the evaluation of the treating physician was used. Furthermore, the efficacy of eribulin was investigated in different tumor subtypes.</p><p><b>Results.</b> Forty-eight patients who received at least one cycle of eribulin were identified. Most patients were heavily pretreated with a median of 3 (range 1–7) previous chemotherapy lines prior to eribulin. Median patient age was 56 years (range 35–74). At the end of the analysis, 23 patients were alive and two were still treated with eribulin. No hypersensitivity reactions and no toxic deaths were seen. Fatigue grade 3–4 was observed in three patients (6.3%). One patient experienced grade 4 neurotoxicity. Grade 3–4 neutropenia was documented in 18.8%, and three patients were treated for a grade 3 infection. Interestingly, three individuals developed Herpes zoster reactivation. One patient responded to treatment with complete remission, while 33.3% had a partial response. 48% of all patients had a clinical benefit (objective response or stable disease for more than six months).</p><p><b>Conclusions.</b> Eribulin administered outside of a clinical trial in patients with advanced breast cancer was safe and well tolerated. A clinical benefit was seen in half of the cases. No statistically significant differences in objective response or survival were observed between histopathological subgroups.</p></div