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Commentary
 
Cancer Immunity, Vol. 5 Suppl. 1, p. 1 (6 April 2005)

Cancer Vaccines 2004 opening address: The molecular and cellular basis of cancer immunosurveillance and immunoediting

Robert D. Schreiber

Center for Immunology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

Keywords:cancer immunosurveillance, cancer immunoediting, immunotherapy, lymphocytes, interferon

 

 

As I began to prepare my presentation for this meeting, I asked my laboratory group to provide me with their simplest definition of the field of tumor immunology. Their answers were very similar. They defined tumor immunology as the study of immune tumor recognition and/or elimination (Figure 1). Continuing with this reductionist approach, I asked them to provide me with the minimum number of possible functional outcomes of immune tumor recognition and elimination. Once again, the members of my lab were in agreement. They felt that there were three, i.e., immune recognition and/or elimination of tumors does happen, cannot happen or can happen.

 


Figure 1

A reductionist view of the field of tumor immunology.

 

 

 

By does happen, we mean that tumors can be recognized and/or eliminated as a result of natural tumor-specific immune responses that develop in the host (Figure 1). This outcome is supported by the findings that (i) the immune system can indeed protect the host against the development of spontaneous and chemically induced tumors, (ii) the immunogenicity of a tumor is often imprinted on it by the immunological environment in which it develops and (iii) individuals with cancer sometimes develop spontaneous reactivity against the antigens of the tumor [reviewed in (1, 2, 3)]. By cannot happen, we mean that many different influences often render a tumor either invisible to the immune system or resistant to its cytocidal functions (Figure 1) [reviewed in (3)]. This situation can occur when the tumor is non-immunogenic, either because it never expressed any tumor antigens or lost them during development, or because it acquired defects in the capacity to present tumor antigens to cells of the immune system (4, 5, 6, 7). In addition, the immune system may not be able to recognize or eliminate a tumor because the tumor itself produces immunosuppressive moieties or induces immunosuppressive responses in the host (8, 9, 10, 11, 12, 13, 14). Finally, tumors may escape immune recognition and/or destruction simply because of their growth characteristics or anatomical location. By can happen, we are referring to the potential beneficial outcomes of immunotherapy (Figure 1) (15, 16). In this scenario, the attention of the immune system is re-directed to the presence of a growing tumor by some form of immunotherapeutic intervention - be it active or passive vaccination with molecules or cells or elimination of immunosuppressive influences either by antibody blockade or cellular depletion (17, 18, 19, 20, 21, 22).

Now this reductionist view of the field, although very much oversimplified, nicely frames the focus of the current meeting. Five talks address the statement that tumor recognition and/or elimination does happen. Two focus on NKT cells (23, 24), two with the interaction between cellular activating receptors and their ligands (25, 26) and one with a mutant mouse that expresses heightened innate immunity against tumor development (27). Interestingly, these talks address aspects of innate immunity to tumors, an area that until recently has not been heavily represented at this meeting in particular or in the field of tumor immunology in general. Three talks address the statement that tumor recognition and/or elimination cannot happen in an otherwise unmanipulated cancer-bearing individual. Two deal with regulatory T cells, their antigens and their capacity to inhibit naturally developing immune responses to tumors (28, 29), while the third deals with immunosuppression arising from signals such as CTLA-4 that inhibit T cell function (30). Finally, eighteen talks are directed at whether immunotherapy can lead to effective immune recognition and/or elimination of tumors. Importantly, these talks provide an excellent summary of the translational and clinical status of our field and also highlight the exciting work that has come out of the Cancer Vaccine Collaborative that is jointly sponsored by the Cancer Research Institute and the Ludwig Institute for Cancer Research. Four talks deal with tumor antigen discovery (31, 32, 33, 34), four with cancer vaccination studies (35, 36, 37, 38), four with new protocols of tumor vaccination (39, 40, 41, 42), two with monitoring the effectiveness of vaccination (43, 44) and four with ongoing clinical trials and attempts to define the mechanisms underlying clinical responses (45, 46, 47, 48).

As my lab and I continued to discuss the focus of this presentation, we were struck by the relevance of this reductionist model to the area of tumor immunology that we work in - the study of natural immune responses to developing primary tumors. This process was originally called "cancer immunosurveillance" but we renamed it "cancer immunoediting" about three years ago so as to better emphasize the fact that the immune system plays a dual role in the process (1, 49). Specifically, the cancer immunoediting hypothesis holds that the immune system not only protects the host against tumor development but can also promote tumor development by selecting for tumor escape variants with reduced immunogenicity. We have since gone on to refine this concept such that we now envisage cancer immunoediting as a process comprised of three phases, which we call the 3 Es of cancer immunoediting (1, 2, 3) (Figure 2). The first phase is called Elimination, which is the same as cancer immunosurveillance, in which cells and molecules of the innate and adaptive immune systems recognize and destroy developing tumors, thus protecting the host against cancer. The second phase is Equilibrium, similar to the concepts of tumor dormancy (50, 51) or viral latency, which is a protracted period in which the tumor and immune system enter into a dynamic equilibrium of tumor destruction and tumor escape. The third phase is Escape, where tumor variants that emerge from a Darwinian-type immune selection process of the equilibrium phase develop into clinically apparent tumors that grow in an unrestricted manner in the immunocompetent host.

 


Figure 2

The three Es of cancer immunoediting: host protective versus tumor sculpting actions of immunity. Following cellular transformation and the failure of intrinsic tumor suppressor mechanisms, a developing tumor is detected by the immune system and its ultimate fate is determined by whether or not it is eliminated by the host protective actions of immunity (Elimination phase), maintained in a dormant or equilibrium state (Equilibrium phase) or escapes the extrinsic tumor suppressor actions of immunity by either becoming non-immunogenic or through the elaboration of immunosuppressive molecules and cells (Escape phase) [adapted from (3)].

 

 

 

When one directly compares the reductionist model of tumor immunology to cancer immunoediting, one sees great conceptual parallels. Specifically, the immune system does protect against tumor development, tumors that are sculpted by their interaction with immunity cannot be rejected in a naive immunocompetent host, yet immunologically-sculpted - or edited - tumors can be eliminated with appropriate immunotherapy. Let me provide you with a few examples that support each statement.

First, I will present data that support the statement that the immune system does protect against tumor development. Over the last 4-5 years, several groups including the groups of Mark Smyth, Adrian Hayday, Rolf Zinkernagel and my own group in collaboration with Lloyd Old have shown that any event that disables innate or adaptive immunity in mice renders them highly susceptible to the development of chemically-induced tumors and to the formation of spontaneous tumors of non-viral origin [reviewed in (2)]. Importantly, as shown in Figure 3, this statement is supported by experiments that employed gene-targeted or transgenic mice with genetically-encoded, developmental immunodeficiencies or wild type mice that developed normally but were then rendered immunodeficient by treatment with neutralizing or blocking monoclonal antibodies specific for distinct molecular or cellular components of the innate or adaptive immune system (52). Using these types of experimental approaches, several immune components (including immunologically important molecules such as IFN-gamma, IL-12, Perforin and TRAIL, or cells such as NK, NKT alpha beta- and gamma delta- cells) were clearly shown to be required for effective cancer immunosurveillance.

 


Figure 3

A plethora of data from many groups supports the existence of a cancer immunosurveillance process in mice. Support comes from the use of gene-targeted mice with congenital immunodeficiencies, as well as using adult wild type mice rendered immunodeficient by injection of neutralizing or depleting antibodies. Together this work shows that loss of either innate or adaptive immunity leads to increased carcinogen-induced and spontaneous tumors in the immunodeficient mice [adapted from (2)].

 

 

 

Here are a few specific examples from our own work that highlight the particularly important roles that lymphocytes and IFN-gamma play in the cancer immunosurveillance process. Shown in Figure 4 is an experiment performed by Vijay Shankaran and Hiroaki Ikeda when they were in my lab in which large groups of age- and sex-matched wild type 129 strain mice or 129 strain mice lacking either RAG2, IFNGR1 (the ligand binding subunit of the IFN-gamma receptor), STAT1 (the transcription factor responsible for inducing many IFN-gamma- and IFN-alpha/beta-dependent biologic responses), or both RAG2 and STAT1 (RkSk mice), were treated with the chemical carcinogen 3’-methylcholanthrene (MCA) and tumor development was monitored over time (49). As can be seen, all of the gene-targeted mice developed 3-5 times more MCA-induced sarcomas than wild type mice. Since there were no significant differences in tumor susceptibility between any of the gene-targeted mice, we concluded that the IFN-gamma/STAT1 and lymphocyte dependent tumor suppressor mechanisms are heavily overlapping.

 


Figure 4

Increased formation of carcinogen-induced sarcomas in immunocompromised mice. Large groups of sex- and age-matched wild type 129 strain mice or 129 strain mice with targeted disruption of the genes for RAG2, IFNGR1 (the ligand binding subunit of the IFN-gamma receptor), STAT1 (the transcription factor critical for IFN-gamma- and IFN-alpha/beta-receptor signaling), or RAG2 plus STAT1, were treated with a 100 µg dose of the chemical carcinogen 3’-methylcholanthrene and tumor formation was followed over time. The final tumor incidences of each group is shown at 160 days [adapted from (49)].

 

 

 

We also examined whether immunologically compromised mice showed an increase in spontaneous tumor formation. To test this possibility, Vijay Shankaran and Allen Bruce set aside several wild type mice, RAG2-/- mice and RkSk mice and followed the development of tumors in the aging population (49) (Figure 5). As seen in the upper panel, the vast majority (9 out of 11) of wild type mice aged 15-21 months showed no evidence of neoplastic disease. One mouse developed a benign Harderian gland cystadenoma at 19 months while another mouse aged 16 months had a premalignant intestinal tubular adenoma, but none of the wild type mice had cancer. In contrast, as shown in the middle panel, 12/12 RAG2-/- mice aged 15-16 months displayed neoplastic lesions. Six were found to harbor adenomas in the intestine that, in humans, are thought to represent precancerous lesions. More importantly, 6 of the older mice in this group (aged 15.8-16.1 months) presented with frank adenocarcinomas. Five had adenocarcinomas of the intestine while one had an adenocarcinoma in the lung. Even more impressive was the analysis shown in the bottom panel of 11 RAG2-/- x STAT1-/- (RkSk) mice housed in the same room. As seen in the bottom panel, all 11 RkSk mice developed neoplastic disease and 9/11 presented with unequivocal carcinomas. The appearance and progression of the tumors in these mice was generally more rapid than that seen in the RAG2-/- mice, with the earliest appearing at 12 months of age. It is interesting that these mice also developed a broader range of tumors compared to the aged mice that lacked Rag2 only. Six of eleven of these mice developed mammary carcinomas and these tumors tended to appear earlier than the intestinal and lung tumors that showed up as well. In addition, the number of mice with multiple tumors also increased. Thus mice that lack either lymphocytes and/or the ability to respond to IFN-gamma show a significantly increased rate of spontaneous tumor formation compared to mice with intact adaptive and innate immune systems.

 


Figure 5

Increased incidence of spontaneous tumors in immunodeficient mice. Eleven to twelve member cohorts of wild type 129 strain mice, or 129 strain mice lacking RAG2 or RAG2 plus STAT1 were set aside to age and tumor incidences followed. At necropsy, mice were scored as either neoplasia-free, positive for adenomatous changes (pre-malignant neoplasia) or positive for unequivocal adenocarcinomas. These results were confirmed subsequently using larger groups [adapted from (49)].

 

 

 

During the last two years, Ruby Chan and Allen Bruce in the lab continued to enroll additional mice into this study and we now have a more complete picture with larger group sizes and longer observation periods (53). Neoplasia remains rare in our 129 strain wild type mice. Although 6/33 wild type mice eventually developed malignancies and another 5 displayed benign tumors, almost all of the disease in affected wild type mice occurred at 26-28 months, which is at the very end of the normal life spans of these mice. Moreover, the tumors appeared in random tissues/organs. In contrast, most of the immunodeficient RAG2-/- mice, IFN-gamma insensitive STAT1-/- mice and the doubly deficient RkSk mice developed cancer much earlier in their life times, with many presenting in what we would call middle age. Interestingly, spontaneous mammary gland tumors were noted in about 50% of aging mice that lack either STAT1 alone or both STAT1 and RAG2, revealing that the mammary gland tumor phenotype tracks with the STAT1 deficiency. Ruby has done a very nice job ruling out the possibility that the high incidence of mammary gland cancer in STAT1 deficient mice was due to viral infection and is currently working on the molecular basis of the disease. Taken together, this work shows that an effective cancer immunosurveillance process is indeed at work in mice.

Although it is not possible to obtain such direct experimental evidence for a cancer immunosurveillance process in humans, strong correlative clinical data has accumulated supporting that a similar process is indeed also operative in humans. Three lines of evidence support this conclusion [reviewed in (2)]. First, several studies have now shown that immunosuppressed transplant patients display a significantly higher susceptibility to the formation of a variety of different cancers of non-viral origin. Second, a positive correlation has been made between the presence and location of T cells - particularly CD8+ T cells - in a tumor and the survival of patients with a variety of different cancers. Third, cancer patients often develop spontaneous immune responses to the tumors that they carry. Thus, the combined work from many labs now strongly supports the statement that immunosurveillance happens.

Second, there is also strong data showing that tumors that are sculpted by their interaction with the immune system cannot be rejected in a naive immunocompetent host. This statement is supported by data from a follow-up study to the MCA carcinogenesis experiment just discussed in which we asked whether similar tumors generated in mice of similar genetic backgrounds that only differed by the presence or absence of an intact immune response displayed differences in their inherent immunogenicities. For this purpose we compared the in vivo growth phenotype of MCA-induced sarcomas derived from immunocompetent wild type mice versus immunodeficient RAG2-/- mice (49). As shown in Figure 6, 17/17 sarcomas derived from wild type mice (panel a) and 20/20 sarcomas from RAG2-/- mice (panel b) grew in an equivalent progressive manner when transplanted into immunodeficient RAG2-/- mice. Thus there are no inherent growth differences between tumors derived from normal and immunodeficient mice. Moreover, as seen in panel c, all 17 sarcomas from wild type mice grew progressively when transplanted into naive wild type mice. In contrast, 40% of the sarcomas that originated in immunodeficient RAG2-/- mice failed to establish progressively growing tumors in naive, syngeneic wild type mice even when injected at high cell numbers (panel d). Thus, chemically-induced tumor cells from immunodeficient RAG2-/- mice are, as a group, more immunogenic than tumors formed in immunocompetent mice. This result showed that the immune system eliminates the most immunogenic cells in a developing tumor and sometimes leaves behind tumor cell variants of reduced immunogenicity that escape immune recognition and/or elimination in the naive host.

 


Figure 6

Tumors derived from immunodeficient mice are highly immunogenic. Seventeen MCA-induced sarcomas from wild type mice (panels a and c) and twenty MCA-sarcomas from RAG2-/- mice (panels b and d) were each injected into five member groups of either immunodeficient RAG2-/- mice (panels a and b) or naive immunocompetent wild type mice (panels c and d). Tumor growth was monitored by daily measurement of tumor size [adapted from (49)].

 

 

 

Third, let me provide an example where effective immunotherapy can lead to immune destruction of an edited tumor. For these studies Dan Kaplan used an MCA-induced fibrosarcoma cell line derived from an IFNGR1-/- mouse called RAD.gR.28 as a model of an edited tumor that was unable to respond to IFN-gamma. When these sarcoma cells were transplanted into immunocompetent mice, they grew in a highly aggressive manner (54) (Figure 7). Allen Bruce in the lab has shown that as few as 10-100 IFN-gamma insensitive RAD.gR.28 cells can form a progressively growing tumor in naive wild type mice. Enforced expression of a cytoplasmically truncated form of IFNGR1 (IFNGR1deltaIC) in RAD.gR.28 cells neither reconstituted IFN-gamma receptor signaling, nor altered the aggressive growth behavior of the tumor. In contrast, complementation with full length, wild type IFNGR1 reconstituted IFN-gamma receptor signaling and tumor immunogenicity such that the tumor cell line was rejected when transplanted into naive syngeneic mice. In subsequent experiments, Vijay Shankaran and Allen Bruce explored what IFN-gamma was doing to tumor cells to alter their immunogenicity (49, 55) (Figure 8). As shown previously, IFN-gamma insensitive RAD.gR.28 tumor cells were highly tumorigenic and poorly immunogenic and thus formed progressively growing tumors when transplanted into naive syngeneic recipients. However, when the tumor cells were engineered for high expression of the MHC Class I components H2-Db or Tap1, they were rendered highly immunogenic and were rejected even when mice were challenged with 3 x 107 cells. The rejection was specific and MHC restricted since the same tumor transduced with H2-Kb was not rejected. Thus appropriate immunotherapy induced rejection of an otherwise non-rejectable tumor.

 


Figure 7

Rejection of IFNGR1 deficient RAD.gR.28 sarcomas following reconstitution of IFN-gamma responsiveness. An MCA sarcoma cell line (RAD.gR.28) from an IFNGR1-/- mouse was transduced either with empty retrovirus (control), a functionally inactive IFNGR1 C-terminal truncation mutant (IFNGR1deltaIC) or wild type IFNGR1. After isolation of homogeneous transduced cell populations, groups of 5 wild type, genetically matched mice were injected with 1 x 106 of each cell type. Tumor growth was quantitated by daily measurement of tumor size [adapted from (54)].

 

 

 


Figure 8

Rejection of Tap1- or H2-Db-reconstituted IFN-gamma-insensitive RAD.gR.28 tumor cells in wild type mice. The RAD.gR.28 tumor cell line used in Figure 7, was transduced with either empty retrovirus or retroviruses encoding H2-Kb, H2-Db or Tap1. After isolating homogeneously expressing cell lines, cells were transplanted into 5-member groups of wild type mice and tumor growth quantitated as described previously [adapted from (49)].

 

 

 

The current research program in my lab is now heavily based on the 3 E model of cancer immunoediting. The efforts of Hiroaki Ikeda, Gavin Dunn and Ravindra Uppaluri in the lab are aimed at understanding the elimination phase and are focused on answering the following questions: What are the key components of innate and adaptive immunity that protect the host against tumor development and how do they function? Catherine Koebel and Kathleen Sheehan in the lab are studying the equilibrium phase and are seeking answers to the questions: Is the immune system indeed capable of maintaining cancer in a dormant state? Does editing occur in the equilibrium phase? What are the molecular targets that are edited and which immune components function as the "editors"? Finally, Jack Bui, Ruby Chan and Mark Diamond in the lab are working to better understand the escape phase by determining the answers to the questions: What are the key alterations that a tumor must undergo to escape immune control? How does this happen? And, can these changes be used to define the extent to which a tumor has been edited so as to identify those patients who would most benefit from immunotherapy?

Let me finish by making a few statements about the implications of this work. First, I think the most significant clinical implication of the cancer immunoediting hypothesis is that most, if not all, tumors that develop in immunocompetent hosts have undergone immunological sculpting. Thus we need to find a way to determine the extent to which a tumor has been edited. Moreover, any immunotherapy regimen needs to take into account that the tumor has already found a way to circumvent immune recognition and elimination. Finally, I propose that if we can indeed obtain hard evidence supporting the existence of the equilibrium phase of cancer immunoediting, then defining the molecular mechanisms that mediate equilibrium may help to identify an additional desirable outcome of cancer immunotherapy. Of course cures are best but - if cancer can’t be eliminated, then perhaps it might be possible to therapeutically maintain it in an induced and durable equilibrium phase. In this manner we may well be able to change the clinical course of a growing tumor - from one that cannot be recognized and/or rejected by immunity to a tumor that can be a target for immunotherapy such that immunity does control or eliminate the tumor and extend the life of the cancer patient (Figure 9).

 


Figure 9

The ultimate goal of tumor immunology. The "Holy Grail" of tumor immunology is harnessing the power of immunity to alter the clinical course of an edited tumor that cannot be recognized and/or rejected by the immune system into one that can be a target and ultimately does get controlled or eliminated in an immunologic manner thereby extending the life of the cancer patient.

 

 

 

Abbreviations

MCA, 3’-methylcholanthrene

 

Acknowledgements

The author is grateful to the many individuals from his lab who participated in these studies over the past 12 years. He is also fortunate to have collaborated with a number of colleagues from his own and other institutions. He is particularly appreciative of the long and productive collaboration and interaction he has had with Dr. Lloyd Old and his colleagues at the New York Branch of the Ludwig Institute for Cancer Research. The work performed in the author’s lab discussed in this review was supported by grants from the National Cancer Institute, the Ludwig Institute for Cancer Research and the Cancer Research Institute.

 

References

1. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991-8. (PMID: 12407406)

2. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22: 329-60. (PMID: 15032581)

3. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004; 21: 137-48. (PMID: 15308095)

4. Algarra I, Cabrera T, Garrido F. The HLA crossroad in tumor immunology. Hum Immunol 2000; 61: 65-73. (PMID: 10658979)

5. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 2000; 74: 181-273. (PMID: 10605607)

6. Seliger B, Maeurer MJ, Ferrone S. Antigen-processing machinery breakdown and tumor growth. Immunol Today 2000; 21: 455-64. (PMID: 10953098)

7. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U S A 2002; 99: 16168-73. (PMID: 12427970)

8. Khong HT, Restifo NP. Natural selection of tumor variants in the generation of "tumor escape" phenotypes. Nat Immunol 2002; 3: 999-1005. (PMID: 12407407)

9. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002; 419: 734-8. (PMID: 12384702)

10. Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Padhajcer OL, Rabinovitch GA. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell 2004; 5: 241-51. (PMID: 15050916)

11. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003; 9: 1269-74. (PMID: 14502282)

12. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999; 59: 3128-33. (PMID: 10397255)

13. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999; 163: 5211-8. (PMID: 10553041)

14. Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, Ikarashi Y, Wakasugi H, Kronenberg M, Nakatama T, Taniguchi M, Kuribayashi K, Old LJ, Shiku H. CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses. Proc Natl Acad Sci U S A 2003; 100: 10902-6. (PMID: 12947044)

15. Old LJ. Immunotherapy for cancer. Sci Am 1996; 275: 136-43. (PMID: 8701283)

16. Rosenberg SA. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 1999; 10: 281-7. (PMID: 10204484)

17. Jager E, Gnjatic S, Nagata Y, Stockert E, Jager D, Karbach J, Neumann A, Rieckenberg J, Chen YT, Ritter G, Hoffman E, Arand M, Old LJ, Knuth A. Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. Proc Natl Acad Sci U S A 2000; 97: 12198-203. (PMID: 11027314)

18. Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses. Science 2004; 305: 200-5. (PMID: 15247469)

19. Skipper J, Hoffman EW, O'Donnell-Tormey J, Old LJ. Translation of cancer immunotherapies. Nat Med 2004; 10: 1154-5. (PMID: 15516901)

20. Pardoll D, Allison J. Translation of cancer immunotherapies. Nat Med 2004; 10: 1155.

21. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002; 3: 611-8. (PMID: 12087419)

22. Dranoff G. CTAL-4 blockade: unveiling immune regulation. J Clin Oncol 2005; 23: 662-4. (PMID: 15613692)

23. Bendelac A. Natural and synthetic antigenic ligands of NKT cells and their role in anti-tumor rejection. Cancer Immun 2005; 5 Suppl 1: 2. URL: http://www.cancerimmunity.org/v5suppl1p2/041223_abs.htm

24. Cerundolo V. Role of NKT cells to assist priming of antigen-specific T-cell response. Cancer Immun 2005; 5 Suppl 1: 3. URL: http://www.cancerimmunity.org/v5suppl1p3/041224_abs.htm

25. Lanier LL. NKG2D-mediated immune responses. Cancer Immun 2005; 5 Suppl 1: 6. URL: http://www.cancerimmunity.org/v5suppl1p6/041227_abs.htm

26. Spies T. Relevance of NKG2D and its ligands in tumor immunity. Cancer Immun 2005; 5 Suppl 1: 10. URL: http://www.cancerimmunity.org/v5suppl1p10/041231_abs.htm

27. Cui Z. "Magic bullets" against cancer cells in cancer-resistant SR/CR mice. Cancer Immun 2005; 5 Suppl 1: 8. URL: http://www.cancerimmunity.org/v5suppl1p8/041229_abs.htm

28. Sakaguchi S, Yamaguchi T, Nishioka T, Ko K, Yamazaki S, Nakamura K, Hirota K, Nomura T. Natural CD4+ regulatory T cells in tumor immunity. Cancer Immun 2005; 5 Suppl 1: 4. URL: http://www.cancerimmunity.org/v5suppl1p4/041225_abs.htm

29. Shiku H. Regulatory T cells recognizing SEREX-defined selfantigens in anti-tumor immune response. Cancer Immun 2005; 5 Suppl 1: 5. URL: http://www.cancerimmunity.org/v5suppl1p5/041226_abs.htm

30. Allison JP. Blockade of T cell inhibitory signals: a new paradigm in tumor immunotherapy? Cancer Immun 2005; 5 Suppl 1: 9. URL: http://www.cancerimmunity.org/v5suppl1p9/041230_abs.htm

31. Valmori D. SSX antigens as cancer vaccines. Cancer Immun 2005; 5 Suppl 1: 18. URL: http://www.cancerimmunity.org/v5suppl1p18/041239_abs.htm

32. Jotereau F. Cross-presentation: a mechanism used by melanoma cells for the generation of a tumor-specific antigen derived from the matrix metalloproteinase 2. Cancer Immun 2005; 5 Suppl 1: 19. URL: http://www.cancerimmunity.org/v5suppl1p19/041240_abs.htm

33. Chen WF. Identification and characterization of human hepatocellular carcinoma-associated antigens. Cancer Immun 2005; 5 Suppl 1: 21. URL: http://www.cancerimmunity.org/v5suppl1p21/041242_abs.htm

34. Güre AO. Immunity to SOX group B and ZIC2 antigens: novel neuro-ectodermal targets and clinical indicators in small cell lung cancer. Cancer Immun 2005; 5 Suppl 1: 20. URL: http://www.cancerimmunity.org/v5suppl1p20/041241_abs.htm

35. Jäger E. Vaccine strategies against NY-ESO-1 in cancer patients. Cancer Immun 2005; 5 Suppl 1: 12. URL: http://www.cancerimmunity.org/v5suppl1p12/041233_abs.htm

36. Davis ID, Chen W, Schnurr M, Hopkins W, Miloradovic L, Old LJ, Maraskovsky E, Cebon JS. NY-ESO-1 protein-based cancer vaccines: the Melbourne experience. Cancer Immun 2005; 5 Suppl 1: 13. URL: http://www.cancerimmunity.org/v5suppl1p13/041234_abs.htm

37. Brichard V. Development of cancer vaccines with the MAGE-3 protein. Cancer Immun 2005; 5 Suppl 1: 16. URL: http://www.cancerimmunity.org/v5suppl1p16/041237_abs.htm

38. Slingluff CL Jr. Melanoma peptide vaccines: multipeptide approaches for targeting cytotoxic and helper T cells. Cancer Immun 2005; 5 Suppl 1: 24. URL: http://www.cancerimmunity.org/v5suppl1p24/041245_abs.htm

39. Schreiber H, Spiotto MT, Rowley DA. Targeting tumor stroma to destroy cancer variants. Cancer Immun 2005; 5 Suppl 1: 7. URL: http://www.cancerimmunity.org/v5suppl1p7/041228_abs.htm

40. Srivastava P. Specific immunogenicity of heat shock protein-peptide complexes: new developments. Cancer Immun 2005; 5 Suppl 1: 11. URL: http://www.cancerimmunity.org/v5suppl1p11/041232_abs.htm

41. Atanackovic D. Danger signals and the development of new cancer vaccine strategies. Cancer Immun 2005; 5 Suppl 1: 17. URL: http://www.cancerimmunity.org/v5suppl1p17/041238_abs.htm

42. Panicali D. The evolution of poxvirus based cancer vaccines. Cancer Immun 2005; 5 Suppl 1: 27. URL: http://www.cancerimmunity.org/v5suppl1p27/041248_abs.htm

43. Chen W, Jackson H, Dimopoulos N, Tai TY, Mifsud NA, Chen Q, Miloradovic L, Maraskovsky E, Old LJ, Davis ID, Cebon JS. Comprehensive analysis of T-cell responses after vaccination with NY-ESO-1 protein. Cancer Immun 2005; 5 Suppl 1: 14. URL: http://www.cancerimmunity.org/v5suppl1p14/041235_abs.htm

44. Speiser DE. Tumor-specific T cells induced in melanoma patients either naturally or by vaccination with peptides, IFA ± CpG oligodeoxynucleotides. Cancer Immun 2005; 5 Suppl 1: 23. URL: http://www.cancerimmunity.org/v5suppl1p23/041244_abs.htm

45. Coulie PG, Lurquin C, Lethé B, van Baren N, Boon T. Possible mechanisms of tumor regression after vaccination with MAGE antigens. Cancer Immun 2005; 5 Suppl 1: 15. URL: http://www.cancerimmunity.org/v5suppl1p15/041236_abs.htm

46. Odunsi K. Lessons from a pilot clinical trial of vaccine therapy with an NY-ESO-1 peptide of dual MHC class I and II specificities in ovarian cancer. Cancer Immun 2005; 5 Suppl 1: 22. URL: http://www.cancerimmunity.org/v5suppl1p22/041243_abs.htm

47. Greenberg P, Ho W, Wolfl M, Teague R, Morimoto J, Dossett M, Blattman J. Isolating tumor-reactive T cells and making them work in tumor therapy. Cancer Immun 2005; 5 Suppl 1: 25. URL: http://www.cancerimmunity.org/v5suppl1p25/041246_abs.htm

48. Dranoff G. GM-CSF based cancer vaccines. Cancer Immun 2005; 5 Suppl 1: 26. URL: http://www.cancerimmunity.org/v5suppl1p26/041247_abs.htm

49. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410: 1107-11. (PMID: 11323675)

50. Wheelock EF, Weinhold KJ, Levich J. The tumor dormant state. Adv Cancer Res 1981; 34: 107-40. (PMID: 7025590)

51. Uhr JW, Tucker T, May RD, Siu H, Vitetta ES. Cancer dormancy: studies of the murine BCL1 lymphoma. Cancer Res 1991; 51: 5045s-53s. (PMID: 1884380)

52. Schreiber RD, Old LJ, Hayday AC, Smyth MJ. Response to 'A cancer immunosurveillance controversy'. Nat Immunol 2004; 5: 4-5.

53. Chan R, Bruce A, Cardiff R, Old LJ, Schreiber RD. Manuscript in preparation.

54. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 1998; 95: 7556-61. (PMID: 9636188)

55. Bruce A, Schreiber RD. Manuscript in preparation.

 

Contact

Address correspondence to:

Robert D. Schreiber, Ph.D.
Center for Immunology, Department of Pathology and Immunology
Washington University School of Medicine
660 South Euclid Avenue, Box 8118
St. Louis, MO 63110
USA
Tel.: + 1 314 362-8747

 

Copyright © 2005 by Robert D. Schreiber