Protein functionality as a potential bottleneck for somatic revertant variants

Transplantation and immunomodulatio

Collective cancer invasion forms an integrin-dependent radioresistant niche

Contains fulltext : 219833.pdf (Publisher’s version ) (Open Access)Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted beta1 and alphaVbeta3/beta5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with beta1 or alphaV integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-beta1/alphaV integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by beta1/alphaVbeta3/beta5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting

Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency

Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC)-derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry, and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modeling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregularly shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection, and class-switching, while in patient 3, high SHM, impaired antigen selection, and class-switching with large single clones imply increased re-cycling of cells within the irregularly shaped GCs. In the lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells are a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flow cytometry, and BCR repertoire analysis contributes to unraveling defects in the essential steps during memory formation.</p