• Kory L. Alderson
  • William J. Murphy
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 633)

1 Memory T Cell Responses and Cancer

While the use of immunotherapy to promote T cell responses for the treatment of certain cancers has made significant progress, it has been hampered with relatively low response rates with regard to overall survival and has been applied to a limited number of cancers. One area that is lacking thus far is an understanding of the importance (or not) of memory T cell generation after immunotherapy in cancer. There are multiple models of memory T cell formation. 1, 2 When properly primed, memory T cells are tenacious and capable effectors that can remove antigen-positive cells before any signs of re-encounter have occurred (Fig.  1). For this reason, the generation of memory T cells in an individual with cancer is desirable for durable and sustained antitumor responses. 1, 2The generation of antigen-specific T cell responses to cancer has been the focus of some groups attempting to increase the numbers of antigen-specific T cells in patients through ex vivo...


Treg Cell Antitumor Response Immunological Memory Immunotherapeutic Agent Immune Repertoire 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Dr. Ruth Gault for her help with figures and Dr. Lisbeth Welniak for her help with reviewing the manuscript. This work was supported in part by R01 CA 95572.


  1. 1.
    June CH. 2007;Adoptive T cell therapy for cancer in the clinic. J Clin Invest 117:1466–1476CrossRefPubMedGoogle Scholar
  2. 2.
    June CH. 2007;Principles of adoptive T cell cancer therapy. J Clin Invest 117:1204–1212CrossRefPubMedGoogle Scholar
  3. 3.
    Robbins PF, Dudley ME, Wunderlich J, et al. 2004;Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 173:7125–7130PubMedGoogle Scholar
  4. 4.
    Morgan RA, Dudley ME, Wunderlich JR, et al. 2006;Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129CrossRefPubMedGoogle Scholar
  5. 5.
    Kershaw MH, Westwood JA, Parker LL, et al. 2006;A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12:6106–6115CrossRefPubMedGoogle Scholar
  6. 6.
    Dudley ME, Wunderlich JR, Robbins PF, et al. 2002;Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854CrossRefPubMedGoogle Scholar
  7. 7.
    Berner V, Liu H, Zhou Q, et al. 2007;IFN-gamma mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy. Nat Med 13:354–360CrossRefPubMedGoogle Scholar
  8. 8.
    Murphy WJ, Welniak L, Back T, et al. 2003;Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses. J Immunol 170:2727–2733PubMedGoogle Scholar
  9. 9.
    Barker BR, Parvani JG, Meyer D, Hey AS, Skak K, Letvin NL. 2007;IL-21 induces apoptosis of antigen-specific CD8+ T lymphocytes. J Immunol 179:3596–3603PubMedGoogle Scholar
  10. 10.
    Damle NK, Leytze G, Klussman K, Ledbetter JA. 1993;Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18-dependent mechanism. Eur J Immunol 23:1513–1522CrossRefPubMedGoogle Scholar
  11. 11.
    Dai Z, Arakelov A, Wagener M, Konieczny BT, Lakkis FG. 1999;The role of the common cytokine receptor gamma-chain in regulating IL-2-dependent, activation-induced CD8+ T cell death. J Immunol 163:3131–3137PubMedGoogle Scholar
  12. 12.
    Zhang J, Bardos T, Shao Q, et al. 2003;IL-4 potentiates activated T cell apoptosis via an IL-2-dependent mechanism. J Immunol 170:3495–3503PubMedGoogle Scholar
  13. 13.
    Zhang J, Xu X, Liu Y. 2004;Activation-induced cell death in T cells and autoimmunity. Cell Mol Immunol 1:186–192PubMedGoogle Scholar
  14. 14.
    Bartholdy C, Kauffmann SO, Christensen JP, Thomsen AR. 2007;Agonistic anti-CD40 antibody profoundly suppresses the immune response to infection with lymphocytic choriomeningitis virus. J Immunol 178:1662–1670PubMedGoogle Scholar
  15. 15.
    Tong AW, Stone MJ. 2003;Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther 10:1–13CrossRefPubMedGoogle Scholar
  16. 16.
    Ishida Y, Agata Y, Shibahara K, Honjo T. 1992;Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895PubMedGoogle Scholar
  17. 17.
    Martin-Orozco N, Wang YH, Yagita H, Dong C. 2006;Cutting edge: programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. J Immunol 177:8291–8295PubMedGoogle Scholar
  18. 18.
    Goldberg MV, Maris CH, Hipkiss EL, et al. 2007;Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood 110:186–192CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang JY, Zhang Z, Wang X, et al. 2007;PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 109:4671–4678CrossRefPubMedGoogle Scholar
  20. 21.
    Chemnitz JM, Eggle D, Driesen J, et al. RNA-fingerprints provide direct evidence for the inhibitory role of TGF{beta} and PD-1 on CD4+ T cells in Hodgkin’s lymphoma. Blood 2007<bib id="bib20_8"> <otherref> Chemnitz JM, Eggle D, Driesen J, et al. RNA-fingerprints provide direct evidence for the inhibitory role of TGF{beta} and PD-1 on CD4+ T cells in Hodgkin&#x2019;s lymphoma. Blood 2007</otherref> </bib> Google Scholar
  21. 21.
    Colley DG, Sasser LE, Reed AM. 2005;PD-L2+ dendritic cells and PD-1+ CD4+ T cells in schistosomiasis correlate with morbidity. Parasite Immunol 27:45–53CrossRefPubMedGoogle Scholar
  22. 22.
    Hatachi S, Iwai Y, Kawano S, et al. 2003;CD4+ PD-1+ T cells accumulate as unique anergic cells in rheumatoid arthritis synovial fluid. J Rheumatol 30:1410–1419PubMedGoogle Scholar
  23. 23.
    Flies DB, Chen L. 2007;The new B7s: playing a pivotal role in tumor immunity. J Immunother 30:251–260CrossRefPubMedGoogle Scholar
  24. 24.
    Okazaki T, Iwai Y, Honjo T. 2002;New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 14:779–782CrossRefPubMedGoogle Scholar
  25. 25.
    Dong H, Strome SE, Salomao DR, et al. 2002;Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800PubMedGoogle Scholar
  26. 26.
    Keir ME, Francisco LM, Sharpe AH. 2007;PD-1 and its ligands in T-cell immunity. Curr Opin Immunol 19:309–314CrossRefPubMedGoogle Scholar
  27. 27.
    Grakoui A, John Wherry E, Hanson HL, Walker C, Ahmed R. 2006;Turning on the off switch: regulation of anti-viral T cell responses in the liver by the PD-1/PD-L1 pathway. J Hepatol 45:468–472CrossRefPubMedGoogle Scholar
  28. 28.
    Khoury SJ, Sayegh MH. 2004;The roles of the new negative T cell costimulatory pathways in regulating autoimmunity. Immunity 20:529–538CrossRefPubMedGoogle Scholar
  29. 29.
    Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. 2003;Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol 171:1272–1277PubMedGoogle Scholar
  30. 30.
    Hori J, Wang M, Miyashita M, et al. 2006;B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. J Immunol 177:5928–5935PubMedGoogle Scholar
  31. 31.
    Picca CC, Larkin J, III, Boesteanu A, Lerman MA, Rankin AL, Caton AJ. 2006;Role of TCR specificity in CD4+ CD25+ regulatory T-cell selection. Immunol Rev 212:74–85CrossRefPubMedGoogle Scholar
  32. 32.
    Barao I, Hanash AM, Hallett W, et al. 2006;Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 103:5460–5465CrossRefPubMedGoogle Scholar
  33. 33.
    33. Beswick EJ, Pinchuk IV, Das S, Powell DW, Reyes VE. B7-H1 expression on gastric epithelial cells after Helicobacter pylori exposure promotes the development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 2007<bib id="bib33_8"> <otherref>33. Beswick EJ, Pinchuk IV, Das S, Powell DW, Reyes VE. B7-H1 expression on gastric epithelial cells after <Emphasis Type="Italic">Helicobacter pylori</Emphasis> exposure promotes the development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 2007</otherref> </bib> Google Scholar
  34. 34.
    Raimondi G, Shufesky WJ, Tokita D, Morelli AE, Thomson AW. 2006;Regulated compartmentalization of programmed cell death-1 discriminates CD4+ CD25+ resting regulatory T cells from activated T cells. J Immunol 176:2808–2816PubMedGoogle Scholar
  35. 35.
    Tarhini AA, Agarwala SS. 2005;Interleukin-2 for the treatment of melanoma. Curr Opin Investig Drugs 6:1234–1239PubMedGoogle Scholar
  36. 36.
    Maker AV, Phan GQ, Attia P, et al. 2005;Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 12:1005–1016CrossRefPubMedGoogle Scholar
  37. 37.
    Tsushima F, Yao S, Shin T, et al. 2007;Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood 110:180–185CrossRefPubMedGoogle Scholar
  38. 38.
    Green DR, Droin N, Pinkoski M. 2003;Activation-induced cell death in T cells. Immunol Rev 193:70–81CrossRefPubMedGoogle Scholar
  39. 39.
    Refaeli Y, Van Parijs L, Alexander SI, Abbas AK. 2002;Interferon gamma is required for activation-induced death of T lymphocytes. J Exp Med 196:999–1005CrossRefPubMedGoogle Scholar
  40. 40.
    Janssen EM, Droin NM, Lemmens EE, et al. 2005;CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434:88–93CrossRefPubMedGoogle Scholar
  41. 41.
    Aggarwal BB. 2003;Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756CrossRefPubMedGoogle Scholar
  42. 42.
    Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H. 2003;Nature’s TRAIL – on a path to cancer immunotherapy. Immunity 18:1–6CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Kory L. Alderson
    • 1
  • William J. Murphy
  1. 1.Department of Microbiology and ImmunologyUniversity of Nevada Reno School of MedicineRenoUSA

Personalised recommendations