ObjectivesWe explored histological and transcriptomic profiles of paired synovial biopsies from rheumatoid arthritis (RA) patients, in order to assess homogeneity in synovial tissue at the individual level.MethodsSynovial biopsies were performed simultaneously in one small and one large joint per patient using needle-arthroscopy for the knee and ultrasound-guided biopsy for the hand or wrist. Synovium from individuals with osteoarthritis was used as controls. Paraffin-embedded samples were stained for CD3, CD20, and CD68. Total RNA was hybridized on high-density microarrays. TCRB variable sequences were obtained from synovial and blood RNA samples.ResultsTwenty paired biopsies from 10 RA patients with active disease were analyzed. Semi-quantification of histological markers showed a positive correlation for synovial hyperplasia, inflammatory infiltrates and CD3-positive T cells between pairs. Pairwise comparison of transcriptomic profiles showed similar expression of RA-related molecular pathways (TCR signaling, T cell costimulation and response to TNFα). T cells clonotypes were enriched in all but one joints compared to blood, regardless of the magnitude of T cell infiltration. Enriched clonotypes were shared between pairs (23–100%), but this was less the case in pairs of joints displaying weaker T cell signatures and more pronounced germinal center-like transcriptomic profiles.ConclusionCellular and molecular alterations in RA synovitis are similar between small and large joints from the same patient. Interindividual differences in magnitude of T cell infiltrates and distribution of enriched T cell clonotypes support the concept of distinct synovial pathotypes in RA that are associated with systemic versus local antigen-driven activation of T cells.
The casein kinase 1 delta (CSNK1D) is a conserved serine/threonine protein kinase that regulates diverse cellular processes including cell cycle progression, circadian rhythm, and neurite outgrowth. Aberrant expression of CSNK1D is described in several cancer types including breast cancer, where it is amplified in about 30% of triple negative breast (TNBC). Here, we have investigated the function of CSNK1D in triple negative cancer cell migration and metastasis.By using immunohistochemistry and in situ hybridization, we found that CNSK1D is highly expressed in primary tumor cells and in tumor cells invading lymphatic nodes compared to non-metastatic tumors. In vitro, knock-down of CSNK1D expression with specific shRNAs in the breast cancer cell line MDA-MB-231 markedly inhibited cancer cell proliferation, invasion and migration and affected the expression of the tight junction proteins claudin 1, occludin and the junction adhesion molecule A. In vivo, the inactivation of CSNK1D reduced lung metastasis in MDA-MB-231 breast cancer xenografts.Altogether, our results indicate that the downregulation of CSNK1D expression inhibits the proliferation and reduces the migration and the metastasis of breast cancer cells. As numerous inhibitors of CSNK1D are currently under development, this might represent an attractive therapeutic target for the treatment of TNBC.
Background: The association of immune checkpoints inhibitors (ICI) and dose dense chemotherapy is a promising combination in a neoadjuvant setting for triple negative breast cancers (TNBC). However, response rates vary from one study to another and timing, best chemotherapy partner and efficacy in breast cancer subtypes considered as less immunogenic, like luminal B tumors, should be further investigated. The B-immune study evaluates a neoadjuvant treatment with paclitaxel followed by a short combination of an anti-PD-L1 antibody with anthracyclines for TNBC and luminal B breast cancers (BC). Method: B-immune (NCT03356860), a multicentric phase Ib/II prospective trial, includes patients with stage I to III luminal B or TNBC treated with paclitaxel 80mg/m2 weekly from week 1 to 12 followed by 4 cycles of epirubicine 90mg/m2 and cyclophosphamide 600 mg/m2 (EC) Q2W in a neoadjuvant setting. The phase Ib evaluated a single infusion of durvalumab (anti-PD-L1) combined with the 3rd cycle of EC. The phase II, in progress, evaluates 2 infusions of durvalumab with the 1st and 3rd cycle of EC respectively. Surgery is planned 3 weeks after the last preoperative treatment. Primary objectives are safety and efficacy based on pathological complete response (pCR) rate. Considering a 2-stage Simon design, 22 TNBC patients are needed in the phase II to detect a pCR rate increase from 30% to 60% and 24 luminal B BC patients are needed to detect a pCR rate increase from 15% to 40% (α = 0.1 and β = 0.1). At least 3 pCRs must be observed among 8 TNBC patients and 2 among 10 Luminal B patients treated in the 1st stage to move to the 2nd stage. Results: This analysis concerns 3 treated patients from phase Ib and 18 from phase II who received the experimental treatment (median age 55 y-old, 10 TNBC, 11 Luminal B, 14% stage I, 67% stage II, 19% stage III). Overall, 169 AEs were reported and 22 (13%) were graded > 2 on 10/21 patients, including 27% of neutropenia (6/22), 22% of anemia (5/22), 13% of severe asthenia (3/22) and 9% of diarrhea (2/22). Four patients (19%) developed thyroid immune endocrine disorders. Efficacy was evaluated on 18 patients included in the 1st stage of phase II (8 TNBC and 10 luminal B). Five among 8 TNBC patients (62%) and 2 among 10 luminal B patients (20%) had a pCR. Conclusions: The B-immune interim analysis reveals an acceptable global safety profile. Reported immune related adverse events were limited to thyroid endocrine disorders. Observed pCR rate after neoadjuvant paclitaxel followed by 2 durvalumab infusions combined to EC chemotherapy warrants pursuing the trial for the TNBC and luminal B cohorts. Citation Format: Javier Carrasco, Claire Quaghebeur, Stephanie Henry, Christine Galant, Mieke Van Bockstal, Paul Delrée, Brigitte Honhon, Dominique Korman, Vincent Verschaeve, Christophe Lonchay, Sarah Levefre, Lionel D'hondt, Martine Berliere, Sophie Delmarcelle, Jean-Michel Mine, Timour Willems, Gebhard Müller, Nathalie Myant, Isabelle Bar, Manuel Constant, Sandy Haussy, Alix Devaux, Pierre Coulie, Jean-Luc Canon, François Duhoux. B-immune interim analysis: A phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-12.
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