IntroductionB-cell non-Hodgkin lymphomas (B-NHLs) are lymphoproliferative malignancies that encompass different biologic and histologic subtypes and arise from mature B cells within secondary lymphoid organs. 1,2 Although these tumors are highly sensitive to both chemotherapy and radiotherapy, 3 the ultimate goal of curing all NHLs remains to be attained. The last 20 years have demonstrated that the chimeric monoclonal antibody (mAb) rituximab has been the most valuable addition to the B-NHL treatment armamentarium. At present, its combination with poly-chemotherapy still represents the standard of choice for the treatment of both indolent and aggressive B-NHL. 4,5 However, given the difficulties in the management of relapse and resistance to rituximab 6,7 and the late toxicities associated with its administration, 8 it seems that treatment of B-NHL may have reached a new plateau. Alternative approaches as well as new molecular targets are thus required to ameliorate management and clinical outcome of the many patients that become resistant to rituximab.We have recently reported that vaccination with autologous dendritic cells (DCs) pulsed with autologous killed tumor cells elicited clinical responses associated with tumor-specific immune activation in 6 of 18 relapsed indolent B-NHL patients. 9 This points to the existence of novel, NHL-restricted therapeutic antigens. Immunohistochemistry (IHC) using patients' circulating immunoglobulins (Igs) on autologous lymphoma biopsies showed that our protocol induced tumor-restricted Ab responses only when it was clinically efficacious. 9 In the present study, we have looked to see whether the antitumor humoral immunity developed in responders was directed against shared NHL-restricted antigen(s). Demonstration of such cross-reactivity constituted the prerequisite for exploitation of the responders' Ab repertoires to discover new lymphoma antigens to be targeted in NHL immunotherapy. We have used an appropriately modified serological proteome-based approach (SERPA) to identify the proteins differentially recognized by these repertoires. HSP105 was one of these proteins. It has been extensively shown that HSP105/110, together with HSP90, HSP70, HSP60, HSP40, and HSP27 classes of proteins, guide the normal folding, intracellular disposition, and proteolytic turnover of many of the key regulators of cell growth, differentiation, and survival, including HER2, mutant HER1, c-KIT, BCR-ABL, Akt, Cdk4, BRAF, HIF1-␣, p53, and other oncoproteins. [10][11][12] Despite the focus on oncogenes as cancer therapy targets, sound experimental evidence demonstrates that targeting stress proteins could also be effective by promoting the destabilization of their client proteins. 10,[13][14][15][16] Our findings show that HSP105 is immunogenic in NHL oncotype and expressed on the plasma membrane and in the For personal use only. on March 28, 2019. by guest www.bloodjournal.org From cytoplasm of human B-NHL cell lines and specimens, with significantly higher intensity in highly proliferating ...