Immune phenotypes and checkpoint molecule expression of clonally expanded lymph node-infiltrating T cells in classical Hodgkin lymphoma

Lymph node-infiltrating T cells have been of particular interest in classical Hodgkin lymphoma (cHL). High rates of complete therapeutic responses to antibody-mediated immune checkpoint blockade, even in relapsed/refractory patients, suggest the existence of a T cell-dominated, antigen-experienced, functionally inhibited and lymphoma-directed immune microenvironment. We asked whether clonally expanded T cells (1) were detectable in cHL lymph nodes, (2) showed characteristic immune phenotypes, and (3) were inhibited by immune checkpoint molecule expression. We applied high-dimensional FACS index sorting and single cell T cell receptor alpha beta sequencing to lymph node-infiltrating T cells from 10 treatment-naive patients. T cells were predominantly CD4(+) and showed memory differentiation. Expression of classical immune checkpoint molecules (CTLA-4, PD-1, TIM-3) was generally low (< 12.0% of T cells) and not different between CD4(+) and CD8(+) T cells. Degrees of clonal T cell expansion varied between patients (range: 1-18 expanded clones per patient) and was almost exclusively restricted to CD8(+) T cells. Clonally expanded T cells showed non-naive phenotypes and low checkpoint molecule expression similar to non-expanded T cells. Our data suggest that the therapeutic effects of immune checkpoint blockade require mechanisms in addition to dis-inhibition of pre-existing lymphoma-directed T cell responses. Future studies on immune checkpoint blockade-associated effects will identify molecular T cell targets, address dynamic aspects of cell compositions over time, and extend their focus beyond lymph node-infiltrating T cells

Millennial-scale fluctuations in Saharan dust supply across the decline of the African Humid Period

The Sahara is the world's largest dust source with significant impacts on trans-Atlantic terrestrial and large-scale marine ecosystems. Contested views about a gradual or abrupt onset of Saharan aridity at the end of the African Humid Period dominate the current scientific debate about the Holocene Saharan desiccation. In this study, we present a 19.63 m sediment core sequence from Lake Sidi Ali (Middle Atlas, Morocco) at the North African desert margin. We reconstruct the interaction between Saharan dust supply and Western Mediterranean hydro-climatic variability during the last 12,000 yr based on analyses of lithogenic grain-sizes, XRF geochemistry and stable isotopes of ostracod shells. A robust chronological model based on AMS 14C dated pollen concentrates supports our multi-proxy study. At orbital-scale there is an overall increase in southern dust supply from the Early Holocene to the Late Holocene, but our Northern Saharan dust record indicates that a gradual Saharan desiccation was interrupted by multiple abrupt dust increases before the ‘southern dust mode‘ was finally established at 4.7 cal ka BP. The Sidi Ali record features millennial peaks in Saharan dust increase at about 11.1, 10.2, 9.4, 8.2, 7.3, 6.6, 6.0, and 5.0 cal ka BP. Early Holocene Saharan dust peaks coincide with Western Mediterranean winter rain minima and North Atlantic cooling events. In contrast, Late Holocene dust peaks correspond mostly with prevailing positive phases of the North Atlantic Oscillation. By comparing with other North African records, we suggest that increases in Northern Saharan dust supply do not solely indicate sub-regional to regional aridity in Mediterranean Northwest Africa but might reflect aridity at a trans-Saharan scale. In particular, our findings support major bimillennial phases of trans-Saharan aridity at 10.2, 8.2, 6.0 and 4.2 cal ka BP. These phases coincide with North Atlantic cooling and a weak African monsoon.Christoph Zielhofer, Steffen Mischke and William Fletcher as principal investigators thank the German Research Foundation (DFG, ZI 721/9-1), the Federal Ministry of Education and Research (BMBF, 01DH17020) and the Natural Environment Research Council (New Investigator Award to W Fletcher, NE/K000608/1, and NERC RCF dating awards, 1765.1013 and 1809.0414) for generous funding of the fieldwork and lab analyses.Peer Reviewe