SYMPOSIUM IN WRITING Todd D. Armstrong ? Beth A. Pulaski Suzanne Ostrand-Rosenberg Tumor antigen presentation: changing the rules Received: 10 October 1997 / Accepted 10 January 1998 AbstractmCell-based tumor vaccines have been developed on the basis of the hypothesis that tumor cells can be genetically modified to present antigen to T lymphocytes directly. Contrary to expectations, cross-priming is the predominant pathway for activation of tumor-specific CD8 + T cells, while direct presentation of antigen dom- inates activation of tumor-specific CD4 + T cells. These results pose interesting paradoxes for the generation of immune responses, and have definite implications for the development of anti-cancer vaccines. Key wordsmTumor antigen presentation ? Immunotherapy ? MHC class II ? Cross-priming ? Cell-based cancer vaccines Introduction Many recently developed cancer immunotherapeutic stra- tegies use tumor cells transfected/transduced with genes encoding molecules that enhance immune responses. These approaches are based on the hypothesis that genetically modified tumor cells will be effective antigen-presenting cells (APC) of tumor-associated antigens (TAA), and that immunization with the modified cells will stimulate a potent antitumor immune response in tumor-bearing indi- viduals. Most approaches focus on activating tumor-speci- fic CD8 + T cells. Some strategies use tumor cells trans- fected/transduced with cytokine genes to enhance CD8 + T cell development, while other strategies use tumor cells transfected with costimulatory molecules to deliver the antigen-specific signal and the second, costimulatory, signal concomitantly to CD8 + T cells (reviewed in [6]). These approaches have shown promising results in animal systems, and several are being tested in clinical trials (http://cancernet.nci.nih.gov). Despite their capacity to enhance cytotoxic T cell (CTL) activity and prolong immune memory, activation of tumor- specific T helper (Th) cells has been less extensively pursued. Immunotherapeutic strategies that have targeted tumor-specific Th cell activation, however, have yielded significant antitumor activity [11, 17, 21, 26]. Several of these studies have used tumor cells transfected with synge- neic MHC class II genes as immunogens to protect naive mice [11, 17, 26] or to treat mice with primary tumors or metastatic disease [3, 32]. Immunotherapy with class-II- transfected tumor cells is based on the hypothesis that the tumor cells present endogenously synthesized tumor pep- tides in the context of MHC class II molecules and efficiently activate tumor-specific CD4 + Th lymphocytes [25, 27]. Although MHC class II molecules usually present exogenously synthesized antigen, there is precedence for the presentation of endogenous antigen [36]. Furthermore, in vitro studies using class-II-transfected mouse tumor cells, demonstrate that, in the absence of the class-II- associated accessory molecules invariant chain and DM, MHC-class II-expressing tumor cells are efficient APC for endogenously synthesized molecules [1]. Activation of tumor-specific CD8 + T cells occurs mostly via cross-priming, while activation of tumor-specific CD4 + T cells is via direct and cross-priming Since the genetic modifications were designed to enhance the antigen-presenting capacity of the tumor cells, it was anticipated that the modified tumor cells would directly present TAA to T lymphocytes (Fig. 1a). Direct antigen presentation by cytokine- and B7-modified tumor cells to CD8 + T cells was particularly expected, because endogen- ously synthesized antigens, such as TAA, normally intersect the MHC-class-I-processing pathway [39], and are pre- This article forms part of the Symposium in Writing on ªTumor and dentritic cells as cellular vaccines: confrontation and perspectivesº, published in this issue (vol 46, no 2) of the journal T.D. Armstrong ? B.A. Pulaski ? S. Ostrand-Rosenberg ( ) Department of Biological Sciences, University of Maryland, Baltimore, MD 21250, USA FAX: +1 410 455 3875 E-mail: srosenbe@umbc.edu Cancer Immunol Immunother (1998) 46: 70 ± 74 Ó Springer-Verlag 1998