Integrated genetic analyses identified T-cell neoplasms other than adult T-cell leukemia/lymphoma in HTLV-1 carriers.2026 · Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Although most T-cell neoplasms that develop in HTLV-1 carriers are considered ATLL, non-ATLL T-cell lymphomas (TCLs) could also occur, as documented in only a few case reports. Herein, we presented 14 cases of non-ATLL TCLs arising in HTLV-1 carriers. All TCL cases were serologically positive for HTLV-1 antibody; Southern blot analysis for the viral integration of HTLV-1, in situ hybridization for HTLV-1 basic leucine zipper factor (HBZ-ISH), quantitative real-time PCR for HTLV-1 proviral load (HTLV-1-qPCR), the entire HTLV-1 genome sequence, and target capture sequencing rigorously excluded the possibility of ATLL. Various histological subtypes, such as six nodal T follicular helper cell lymphomas, angioimmunoblastic type/not otherwise specified (nTFHL-AI/NOS), two monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL), two peripheral T-cell lymphomas, NOS (PTCL, NOS), and two anaplastic large cell lymphomas (ALCL), ALK-negative, were included. Each case exhibited immunophenotypes and genetic profiles consistent with its respective histological subtype, but atypical for ATLL. Three nTFHL-AI cases exhibited co-mutations of RHOA p.G17V, TET2, and IDH2 p.R172, characteristic of nTFHL-AI but not of ATLL. Among the molecular analytic modalities included in this study, the combination of HBZ-ISH and HTLV-1-qPCR represented the results obtained from the other more expensive modalities, indicating that this combination is effective in daily practice. When T-cell neoplasms arise in HTLV-1 carriers and exhibit atypical clinical, phenotypical, or genetic features for ATLL, it is recommended to perform HBZ-ISH and HTLV-1-qPCR to distinguish non-ATLL TCLs.
Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade2025 · Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.
Genomic Features of Cervical Cancer in Okinawa, Japan: Preliminary Findings From 23 Patients2025 · Background/Aim: Regional differences in genomic mutation profiles of uterine cervical cancer have been reported. Japanese people are divided into two genetic background clusters, originating from mainland Japan and Okinawa. Okinawa is an island prefecture surrounded by the sea, located more than 800 km from the southernmost point of mainland Japan. No studies have examined gene mutation profiles of cervical cancer in Okinawa. This study aimed to investigate the mutation profile of cervical cancer in Okinawa. Patients and Methods: Twenty‑three patients with biopsy‑proven squamous cell carcinoma and adenocarcinoma of the intact uterine cervix who were treated with definitive radiotherapy were analyzed. Genomic DNA was extracted from fresh frozen tissue samples collected by tumor biopsy prior to treatment. Variants of 224 cancer‑related genes were identified using next‑generation sequencing. Results: A total of 29 gene mutations were observed in 16 patients, including nine genes mutated in multiple samples: SCN7A (17%), PIK3CA (13%), FGFR4 (13%), USP6 (13%), SETD2 (9%), KIT (9%), TSC1 (9%), SERPING1 (9%), and NOTCH3 (9%). Compared to a report from mainland Japan, significant differences in mutation frequency were observed in PIK3CA, FBXW7, and ARID1A. Significant mutations in ARID1A, FBXW7, PTEN, TP53, and EP300, reported as relatively common in cervical cancer in other regions were not detected in this study. The rate of 2‑year overall survival and progression‑free survival was 95.5% and 73.4%, respectively. Conclusion: Gene mutation profiles of cervical cancer in Okinawa may differ from those in other regions.
Recent progress in pathological understanding of adult T-cell leukemia/ lymphoma in the new classification era2025 · Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by Human T-cell leukemia virus type 1 (HTLV-1) infection. Although the 5th Edition of the WHO classification (WHO-5) did not make drastic changes regarding the disease concept of ATLL from the revised 4th Edition of the WHO classification (WHO-4R), WHO-5 newly introduced the essential and desirable diagnostic criteria, namely, "neoplastic lymphoid cell proliferation with mature T-cell phenotype; proven HTLV-1 carriership" and "identification of monoclonal integration of HTLV-1", respectively. To satisfy the desirable criteria, a new diagnostic method using a combination of HBZ-ISH and tax-PCR was introduced for the identification of the HTLV-1 in addition to the conventionally used Southern blot hybridization, especially in the case when only FFPE specimens are available. Morphologically, pleomorphic- and anaplastic large cell-type, account for most cases, while minor variants, ATLL with dermatopathic reaction, angioimmunoblastic T-cell lymphoma-like variant, and classic Hodgkin lymphoma-like variant, should also be noted as diagnostic pitfalls. Phenotypically, about 80 % of ATLL cases show a typical phenotype of CD3 + CD4 +CD25 +CCR4 + , while about 10 % show atypical phenotypes such as T follicular helper cell-like one. Many genetic abnormalities, mainly associated with the TCR signaling pathway, are observed, and most are more frequent in the aggressive type than in the indolent type, except for STAT3, indicating the heterogeneous pathogenic process of ATLL. In this review, we present the latest findings on molecular pathogenesis and histopathological findings of ATLL in the era of the new classification of lymphomas, serving as a basis for future research and classification.
