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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4364-4365. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Zitvogel, L. Articles by Kroemer, G. PubMed PubMed Citation Articles by Zitvogel, L. Articles by Kroemer, G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Zebedin et al, page 4655 The dilemma of anticancer therapy: tumor-specific versus immune effects Laurence Zitvogel, and Guido Kroemer INSTITUT GUSTAVE ROUSSY The PI3K isoform is required for both optimal growth of Abelson-transformed leukemia cells and antileukemic NK-cell effectors. Therefore, the simultaneous inhibition of PI3K in tumor and host cells results in therapeutic failure. Deregulation of the phosphoinositide 3-kinase (PI3K) pathway can occur by activating mutations in growth factor receptors or in the PIK3CA locus coding for PI3K, by loss of function of the lipid phosphatase PTEN, by up-regulation of protein kinase B (PKB/Akt), or by the impairment of the tuberous sclerosis complex (TSC1/2). All these events stimulate cancer growth and proliferation and have thus prompted a major interest in therapeutic inhibition of the PI3K pathway. One particular PI3K isoform, PI3K, is selectively expressed in leukocytes and, hence, might constitute a pharmacologic focus for the "targeted" treatment of hematological malignancies. In an elegant study published in the present issue of Blood, Zebedin and colleagues explore the effect of the PI3K knockout on Abelson virus (cAbl)–induced leukemia in mice. For this, PI3K was either removed from the transformed cells themselves, or from the host environment into which transformed cells were injected. These experiments reveal a formidable contradiction. PI3K deficiency in leukemic cells retarded tumor progression while PI3K deficiency in nonleukemic host cells accelerated the fatal course of leukemia. Intriguingly, the simultaneous removal of PI3K from leukemic cells and the host had no effect on leukemic progression at all. This latter result suggests that complete and selective pharmacologic PI3K inhibition (something that obviously would affect both tumor and host cells) would have no therapeutic benefit on PI3K-overexpressing Bcr/abl-positive human leukemias. Zebedin et al also show that PI3K–/– mice exhibit an accelerated development of cancers that are usually controlled by natural killer (NK) cells, such as Abelson-transformed cells, Eµ-myc–induced B-cell lymphoma, EL4 thymoma, and B16 melanoma. These PI3K effects were also found on a RAG2–/– background, indicating that they must involve other immune effectors besides B or T lymphocytes. Indeed, PI3K–/– NK cells poorly lysed leukemic cells, correlating with a general defect in exocytosis that affects both degranulation and IFN secretion. Although formal proof that accelerated tumor progression must be attributed to this NK defect is elusive, these results make it highly plausible that PI3K-dependent effectors of the innate immune system play a major role in tumor control. The results by Zebedin et al contribute to a general debate on the mechanisms through which anticancer chemotherapeutics (fail to) act. Accumulating evidence indicates that radiotherapy and some chemotherapeutic agents, in particular anthracyclines, can trigger specific immune responses that result either from immuno-genic cancer cell death or from immuno-stimulatory off-target effects. This anticancer immune response then helps to eliminate residual cancer cells (that failed to be killed by chemotherapy) or maintain micrometastases (or perhaps cancer stem cells) in a stage of dormancy.1 Ideally, anticancer chemotherapeutics should induce a cellular stress response and/or immunogenic cancer cell death that trigger an effective immune response. Genotoxic agents induce NKG2D ligands through an ATM-dependent and Chk1- dependent DNA damage pathway.2 Such NKG2D ligands on the surface of tumor cells then permit their lysis by NK cell–expressing (and possibly CD8+T cell)–expressing NKG2D. Similarly, multiple chemotherapeutics stimulate the expression of death receptors (such as Fas/CD95 or TRAIL receptors) that facilitate the induction of apoptosis by immune cells.1 Another example is provided by calreticulin (and perhaps other chaperones) that is exposed on the surface of anthracycline-treated tumor cells before they undergo apoptosis, thereby facilitating their uptake by dentritic cells (DCs) which, in turn, present tumor antigen to cytotoxic T lymphocytes.3 View larger version (37K): [in this window] [in a new window]   Best case scenario for anticancer therapy with respect to immune effectors. The cytostatic or cytotoxic agent should (A) stimulate a cell-autonomous response that facilitates recognition (and ultimately lysis) of tumor cells by immune effectors and (B) have immunostimulatory "side effects" on the host that boost the innate and/or cognate immune anticancer response. The incapacity to mediate such effects or worse, immunosuppressive side effects, can entail therapeutic failure.   In addition, the ideal anticancer agent should exert direct immunostimulatory effects on immune effectors. Nontargeted genotoxic anticancer agents often impair the immune system through the induction of myelosuppression and through the elimination of proliferating lymphocytes or other immune effectors. However, some targeted agents, such as the tyrosine kinase inhibitor imatinib mesylate, can activate NK cells4 and expand specific NK-cell subpopulations with potent antitumor effects.5 Thus, in vivo administration of imatinib can trigger the NK cell–dependent control of cancers that do not respond to imatinib in vitro.4 Conversely, another tyrosine kinase inhibitor, sorafenib, strongly inhibits T-cell activation by DCs and, hence, might subvert the anticancer immune response.6 Moreover, specific inhibitors of the lipid kinase PI3K — which have been initially developed as immunosuppressive agents for the treatment of autoimmune disease7 — can compromise multiple immune effectors including NK cells, as demonstrated by Zebedin et al, as well with disastrous consequences for anticancer therapies. Altogether, this scenario should stimulate careful monitoring of positive or negative immunologic effects exerted by targeted anticancer agents, both in animal models and in clinical trials. Therapeutic success of cancer therapies definitively depends on their direct or indirect effects on DC, T, and NK cells. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8:59–73.[CrossRef][Medline] [Order article via Infotrieve] Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 2005;436:1186–1190.[CrossRef][Medline] [Order article via Infotrieve] Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61.[CrossRef][Medline] [Order article via Infotrieve] Borg C, Terme M, Taieb J, et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest. 2004;114:379–388.[CrossRef][Medline] [Order article via Infotrieve] Taieb J, Chaput N, Menard C, et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med. 2006;12:214–219.[CrossRef][Medline] [Order article via Infotrieve] Hipp MM, Hilf N, Walter S, et al. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood. 2008;111:5610–5620.[Abstract/Free Full Text] Camps M, Ruckle T, Ji H, et al. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med. 2005;11:936–943.[Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Leukemic challenge unmasks a requirement for PI3K in NK cell–mediated tumor surveillance Eva Zebedin, Olivia Simma, Christian Schuster, Eva Maria Putz, Sabine Fajmann, Wolfgang Warsch, Eva Eckelhart, Dagmar Stoiber, Eva Weisz, Johannes A. Schmid, Winfried F. Pickl, Christian Baumgartner, Peter Valent, Roland P. Piekorz, Michael Freissmuth, and Veronika Sexl Blood 2008 112: 4655-4664. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Zitvogel, L. Articles by Kroemer, G. PubMed PubMed Citation Articles by Zitvogel, L. Articles by Kroemer, G. 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