Summary There is little insight into or agreement about the signals that control differentiation of memory B cells (MBC) and long-lived plasma cells (LLPC). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPC in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed observations in wild type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergo a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPC at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, vaccine development, and for understanding long-term pathogen resistance.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

Memory B cells (MBCs) are long-lived sources of rapid, isotype-switched secondary antibody-forming cell (AFC) responses. Whether MBCs homogeneously retain the ability to self-renew and terminally differentiate or if these functions are compartmentalized into MBC subsets has been unclear. It was previously suggested that antibody isotype controls MBC differentiation upon restimulation. Here we demonstrate that subdividing MBCs based on expression of CD80 and PD-L2, independent of isotype, identified MBC subsets with distinct functional behaviors upon rechallenge. CD80+PD-L2+ MBCs differentiated rapidly into AFCs but did not generate germinal centers (GCs); conversely CD80−PD-L2− MBCs generated few early AFCs but robustly seeded GCs. Gene expression patterns of subsets support both the identity and function of these distinct MBC types. Hence, MBC differentiation and regeneration are compartmentalized.

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

The adoptive transfer of antigen-specific B cells into mice that cannot recognize that specific antigen has two main advantages. The first is determining exactly when the B cells were transferred and exposed to antigen. The second is that all B cells that can bind that antigen are the ones that were transferred; no new antigen-specific B cells will emerge from the bone marrow. Thus all B cells that were exposed to the antigen and still alive after at least 4 weeks (8 weeks or more is ideal), are memory B cells. Materials and Reagents A.Mice Any donor mice can be used, as long as the donor and recipients have the same background strain (i.e. BALB/C into BALB/c or Bl/6 into Bl/6) to prevent rejection issues. We selected transgenic donor mice that had an increased frequency of B cells specific for our antigen of interest, NP. This way we could be certain of the number of B cells specific for our antigen and these would be easy to identify by flow cytometry and elispot. However, wild-type mice will also respond to NP, just at a lower frequency.

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