Summary: Three recent studies, approaching the question from different angles and using different and/or overlapping models, provide compelling evidence for the involvement of tumor-infi ltrating B cells in the initiation and progression of pancreatic ductal adenocarcinoma. These studies highlight the need for a better understanding of pancreatic tumor-immune system interactions and the immunologic mechanisms that promote or inhibit tumorigenesis, paving the way for better treatment strategies. Cancer Discov; 6(3); 230-2. ©2016 AACR.See related article by p. 247 (8).See related article by Lee et al., p. 256 (9).See related article by Gunderson et al., p. 270 (10).Treatment of pancreatic cancer has proven very diffi cult because of both the low/nonimmunogenic nature of the tumor and the late stages at diagnosis. This is refl ected in the abysmal 5-year survival rate of ∼ 7% and the harsh standard-of-care (SOC) for patients. The most common treatment, aside from palliative care or surgery in eligible patients, is gemcitabine, which is a general DNA-damaging agent. However, those patients healthy enough to handle strong treatment side effects are given a cocktail of four drugs called FOLFIRINOX in the hope of stalling tumor development. Other FDA-approved drug combinations may be tried as the fi rst-line treatment, but all have signifi cant side effects affecting patient quality of life without much measurable benefi t. Although no immunotherapies are currently approved for treating pancreatic cancers, there are 16 clinical trials of various immunotherapies for this disease (clinicaltrials. gov). These trials fall into two categories: combination therapies and vaccines. Most of the combination therapies involve adding an immunotherapy-like checkpoint blockade, vaccine, or cytokines to the SOC, aiming to fi rst make pancreatic ductal adenocarcinoma (PDAC) immunogenic and then promote antitumor immune responses ( 1 ).Studies in both human and animal models have now demonstrated that the immune system plays a critical role in modulating the outcome of tumor development. In general, cytotoxic CD8 + T cells, Th1-type CD4 + T cells, and natural killer (NK) cells exhibit antitumor activity, whereas regulatory T cells, myeloid-derived suppressor cells (MDSC), and tumorassociated macrophages (TAM) suppress antitumor immune responses and promote tumor progression and metastasis ( 2 ). Increasingly, B cells are also found to play a signifi cant role in modulating the growth and progression of solid tumors ( 2, 3 ). Tumor-infi ltrating lymphocytic B cells (TIL-B) are a major component of TILs in breast and advanced ovarian cancers, and their presence correlates with improved survival. However, in multiple mouse models, tumor development is enhanced when B cells are present. Growth of EL4 thymoma, MC38 colon cancer, and EMT6 breast cancer is signifi cantly inhibited in B cell-defi cient mice. The absence of B cells is associated with increased infi ltration of Th1 cells, CD8 + T cells, and NK cells in the tumor. Conversely, ad...