Long-term outcome of 9G MRI-guided vacuum-assisted breast biopsy: results of 293 single-center procedures and underestimation rate of high-risk lesions over 12 years.

PURPOSE: Breast magnetic resonance imaging (MRI) can detect some malignant lesions that are not visible on mammography (MX) or ultrasound (US). If a targeted, second-look fails, MRI-guided breast biopsy is the only available tool to obtain a tissue sample and pathological proof of these "MRI-only lesions". The aim of this study is to report the performance and underestimation rate of 9G MRI-guided vacuum-assisted breast biopsy (VABB) over 12 years at a single center. MATERIAL AND METHODS: All 9G MRI-VABB procedures performed from January 2010 to December 2021 were retrospectively reviewed. Two MRI scanners (1.5 T and 3 T) were used with the same image resolution and contrast media. All suspicious lesions detected only by breast MRI underwent biopsy. Reference standard was histological diagnosis or at least 1-year negative follow-up. All malignant and atypical lesions underwent surgery, which was used as the reference standard. RESULTS: A total of 293 biopsies were retrospectively reviewed. Histopathological VABB results revealed 142/293 (48.4%) benign lesions, 77/293 (26.2%) high-risk lesions, and 74/293 (25.2%) malignant lesions. No significant complications were observed. Surgical pathology results allowed for the reclassification of n = 7/48 B3b lesions: n = 4 were ductal carcinoma in situ, while n = 3 presented invasive features at surgical histology (2 IDC; 1 ILC). B3b underestimation occurred overall in 14.6% of B3 cases. Breast follow-up was achieved for all benign VABB results, and only one false-negative case was observed. CONCLUSION: Our results confirm that 1.5 T and 3 T MRI-guided VABB is an accurate and safe procedure for histopathologic final diagnosis of MRI-only lesions. Critical issues remain the potential high-risk underestimation rate of B3b VABB results and management of follow-up of benign lesions.

mTOR-dependent translation drives tumor infiltrating CD8+ effector and CD4+ Treg cells expansion.

We performed a systematic analysis of the translation rate of tumor-infiltrating lymphocytes (TILs) and the microenvironment inputs affecting it, both in humans and in mice. Measurement of puromycin incorporation, a proxy of protein synthesis, revealed an increase of translating CD4+ and CD8+ cells in tumors, compared to normal tissues. High translation levels are associated with phospho-S6 labeling downstream of mTORC1 activation, whereas low levels correlate with hypoxic areas, in agreement with data showing that T cell receptor stimulation and hypoxia act as translation stimulators and inhibitors, respectively. Additional analyses revealed the specific phenotype of translating TILs. CD8+ translating cells have enriched expression of IFN-γ and CD-39, and reduced SLAMF6, pointing to a cytotoxic phenotype. CD4+ translating cells are mostly regulatory T cells (Tregs) with enriched levels of CTLA-4 and Ki67, suggesting an expanding immunosuppressive phenotype. In conclusion, the majority of translationally active TILs is represented by cytotoxic CD8+ and suppressive CD4+ Tregs, implying that other subsets may be largely composed by inactive bystanders.

The P2X7 Receptor in Tumor Immunity.

Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.

P2X7 Receptor Activity Limits Accumulation of T Cells within Tumors.

Extracellular ATP (eATP) is a signaling molecule that variably affects all cells of the immune system either directly or after hydrolysis to adenosine. Although eATP is virtually absent in the interstitium of normal tissues, it can be present in the hundreds of micromolar range in tumors, a concentration compatible with activation of the ATP-gated ionotropic P2X7 receptor. Here, we show that P2X7 activity in tumor-infiltrating lymphocytes (TIL) induces cellular senescence and limits tumor suppression. P2X7 stimulation affected cell cycling of effector T cells and resulted in generation of mitochondrial reactive oxygen species and p38 MAPK-dependent upregulation of cyclin-dependent kinase inhibitor 1A (Cdkn1a, encoding for p21Waf1/Cip1). Lack of P2X7 promoted a transcriptional signature that correlated with enhanced cytotoxic T-cell response in human solid tumors. In mice, transfer of tumor-specific T cells with deletion of P2rx7 significantly reduced tumor growth and extended survival. Collectively, these findings uncover a purinergic checkpoint that can be targeted to improve the efficacy of cancer immunotherapy strategies. SIGNIFICANCE: These findings suggest that the purinergic checkpoint P2X7 may be targeted to enhance T-cell-mediated cancer immunotherapy and improve T effector cell accumulation in the tumor microenvironment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3906/F1.large.jpg.

P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus.

Altered control of T follicular helper (Tfh) cells can lead to generation of autoantibodies and autoimmune manifestations. Signaling pathways that selectively limit pathogenic responses without affecting the protective function of Tfh cells are unknown. Here we show that the ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant Tfh cells and the generation of self-reactive antibodies in experimental murine lupus, but its activity is dispensable for the expansion of antigen-specific Tfh cells during vaccination. P2X7 stimulation promotes caspase-mediated pyroptosis of Tfh cells and controls the development of pathogenic ICOS+ IFN-γ-secreting cells. Circulating Tfh cells from patients with systemic lupus erythematosus (SLE) but not primary antiphospholipid syndrome (PAPS), a nonlupus systemic autoimmune disease, were hyporesponsive to P2X7 stimulation and resistant to P2X7-mediated inhibition of cytokine-driven expansion. These data point to the P2X7 receptor as a checkpoint regulator of Tfh cells; thus, restoring P2X7 activity in SLE patients could selectively limit the progressive amplification of pathogenic autoantibodies, which deteriorate patients' conditions.