Eletters

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Science in Medicine
To kill a tumor cell: the potential of proapoptotic receptor agonists
Avi Ashkenazi, Roy S. Herbst
J. Clin. Invest. 2008; 118(6):1979

The immune system: an ally in TRAIL-based cancer therapy?

Veronica Huber | veronica.huber@istitutotumori.mi.it

Other authors: Manuela Iero, Paola Filipazzi, Giorgio Parmiani, and Licia Rivoltini

Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Published on July 17, 2008

With great interest we read about the advances in cancer therapy using proapoptotic receptor agonists (1). Indeed, TRAIL and its death receptors have entered clinical studies and are gaining increased interest over the last few years. Numerous agonist antibodies targeting the death receptors for TRAIL are currently tested in Phase I-II clinical trials including the most diverse cancer histotypes. These therapies, which are apparently safe and well-tolerated, seem to mediate some clinical benefit in selected patients, in terms of disease stabilization or objective responses. These encouraging results open novel and attractive strategies for the treatment of several types of cancer.

However, not much light has been shed so far on the mechanisms involved in such clinical outcome. In truth, tumor cells are often found in vitro to be resistant to TRAIL-induced apoptosis or lack appropriate receptor expression when cancer lesions are analyzed. Indeed, if retrospectively tested, only a small percentage of tumors specimens express TRAIL death receptors, thus making it complex to understand how they can efficiently be targeted by specific antibodies (2). A direct killing of tumor cells by activation of apoptotic processes seems therefore unlikely to be the only effect attributed to this therapeutic approach. In this context we deem reasonable to hypothesize that the anti-tumor effect of TRAIL-based therapies might also depend on some previously unexpected consequences that these treatments play on immune cells. In fact, TRAIL is now emerging as a key player in regulating immune responses (3,4). Results are still controversial, but it seems that at certain stages of their activation process and especially under disease conditions, T cells gain sensitivity to TRAIL through the expression of cognate death receptors (5-7). In vivo administration of TRAIL receptor agonist antibodies could therefore involuntarily target immune cells, too, with different and unpredictable immunological outcomes depending on their functions and activation state. For instance, TRAIL triggering could contribute to the down-regulation of regulatory T cells leading to the recovery of anti-tumor T cell responses and immune mediated tumor regressions (8). On the other hand, TRAIL-mediated elimination of immune effectors, meaning tumor-specific CD8 T cells (3) or crucial mediators of antigen processing and presentation, like DCs (9), could instead contribute in tilting the balance thereby favouring disease progression due to depressed tumor immunity.

In view of this, we would like to encourage the introduction of studies aimed at evaluating potential effects of such therapies on immune cells. This may provide a more exhaustive picture of the mechanisms by which therapies targeting TRAIL death receptors may affect tumor growth in cancer patients.

References

  1. Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest. 2008;118:1979-90
  2. Tolcher AW, Mita M, Meropol NJ, von Mehren M, Patnaik A, Padavic K, Hill M, Mays T, McCoy T, Fox NL, Halpern W, Corey A, Cohen RB. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol. 2007;25:1390-5
  3. Zhang XR, Zhang LY, Devadas S, Li L, Keegan AD, Shi YF. Reciprocal expression of TRAIL and CD95L in Th1 and Th2 cells: role of apoptosis in T helper subset differentiation. Cell Death Differ. 2003;10:203-10
  4. Ren X, Ye F, Jiang Z, Chu Y, Xiong S, Wang Y. Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4(+)CD25(+) regulatory T cells. Cell Death Differ. 2007;14:2076-84
  5. Clancy L, Mruk K, Archer K, Woelfel M, Mongkolsapaya J, Screaton G, Lenardo MJ, Chan FK. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci U S A. 2005;102:18099-104
  6. Janssen EM, Droin NM, Lemmens EE, Pinkoski MJ, Bensinger SJ, Ehst BD, Griffith TS, Green DR, Schoenberger SP. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature. 2005;434:88-93
  7. Jeremias I, Herr I, Boehler T, Debatin KM. TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur J Immunol. 1998;28:143-152
  8. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775-87
  9. You RI, Chang YC, Chen PM, Wang WS, Hsu TL, Yang CY, Lee CT, Hsieh SL. Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3). Blood 2008;111:1480-1488


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