603:, but rather involves injection of tumor cells which have been transfected to express MHC class II molecules, in addition to suppression of the invariant chain (Ii, see below) through antisense technology. (Qiu, 1999) Mice vaccinated with irradiated strains of these cells show a greater immune response to subsequent challenge by the same tumor, without the upregulation of MHC class II, then do mice vaccinated with irradiated, but otherwise unaltered tumor cells. These findings signify a promising area of future research in the development of cancer vaccines.
634:
II expression. (Trincheiri and
Perussia, 1985, Fransen L, 1986) A second, more effective approach involves targeting the genes responsible for the synthesis of these proteins, the CIITA or class II transcription activator. Selective gene targeting of CIITA has been used ex vivo to allow MHC class II cells to become MHC class II (Xu, et al. 2000). upregulation of CIITA also causes an increased expression of Ii, and as such, must be used in conjunction with the antisense techniques referred to earlier (Qui, 1999). In some forms of cancer, such as
318:(Abbas and Lichtman, 2005), yet here they were seen at nearly equal levels. Even more interesting was the fact that both these cytokines were required for maximal tumor immunity, and that mice deficient in either showed greatly reduced antitumor immunity. IFN-γ null mice showed virtually no immunity, while IL-4 null mice showed a 50% reduction when compared to immunised
574:) has been observed in IFNγ mice although levels of macrophages at the site of tumor challenge are similar to wild type mice. INOS mice also show decreased immunity, indicating a direct role of CD4-stimulated iNOS production in protection against tumours. (Hung et al., 1998) Similar results have been seen in
1181:
Dranoff, G., Jaffee, E., Lazenby, A., Golumbek, P., Levitsky, H., Brose, K., Jackson, V., Hamada, H., Pardoll, D. and
Mulligan, R., 1993. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting
241:. Detailed explanations of these tumor antigens can be found in Abbas and Lichtman, 2005. MHC class II restricted antigens currently remain somewhat obscure. Development of new techniques has been successful in identifying some of these antigens, however, additional research is required. (Wang, 2003)
1243:
Morimoto et al., 2004 Y. Morimoto, M. Toyota, A. Satoh, M. Murai, H. Mita, H. Suzuki, Y. Takamura, H. Ikeda, T. Ishida, N. Sato, T. Tokino and K. Imai, Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-gamma
554:
A number of mechanisms have been proposed to explain the role of IFN-γ in antitumor immunity. In conjuncture with TNF (Tumor
Necrosis Factors), IFN-γ can have direct cytotoxic effects on tumor cells (Franzen et al., 1986) Increased MHC expression, as a direct result of increased IFN-γ secretion, may
273:
The role of CD4 T cells in antitumor immunity is controversial. It was suggested that CD4 T cells can have a direct role in antitumor immunity through direct recognition of tumor antigens presented on the surface of tumor cells in association with MHC class II molecules. Of note, results from recent
633:
of these proteins does not provide a practical method for use as a cancer vaccine. (Chamuleau et al., 2006) Alternately, two other methods have been examined to upregulate the expression of these proteins on MHC class II cells. The first is treatment with IFNγ, which can lead to increased MHC class
611:
The down regulation of the invariant chain (Ii) becomes important when considering the two pathways by which antigens are presented by cells. Most recognized tumor antigens are endogenously produced, altered gene products of mutated cells. These antigens, however, are normally only presented by MHC
159:
when compared to tumors which have been grown in immunodeficient mice (Shankaran et al., 2001) Three possible outcomes for tumors managing to evade the immune system, and reach the equilibrium phase have been proposed: 1) eventual elimination by the immune system 2) a prolonged or indefinite period
585:
In 2000, Qin and
Blankenstein, showed that IFNγ production was necessary for CD4 T cell-mediated antitumor immunity. A series of experiments showed that it was essential for nonhematopoietic cells at the site of challenge, to express functional IFNγ receptors. Further experiments showed that IFN-γ
257:
by MHC class II, however, most cells express only MHC class I; second, CD8 T cells, upon being presented with antigen by MHC class I, can directly kill the cancerous cell, through mechanisms which will not be discussed in this article, but which have been well categorized; (See Abbas and
Lichtman,
333:
progenitor cells into eosinophils, less eosinophils are seen at the site of tumour challenge, which is to be expected. (Hung, 1998) These mice also show reduced antitumor immunity, suggesting that IL-4 deficient mice, which would produce less IL-5, and subsequently have reduced eosinophil levels,
616:
of the cell, in which MHC class I, MHC class II and endogenously synthesized antigenic proteins are all present. These antigen proteins are prevented from binding to MHC class II molecules by a protein known as the invariant chain or Ii, which, in a normal cell, remains bound to the MHC class II
598:
of tumors by APCs and subsequent presentation on MHC class II. It is rare that tumor cells will express sufficient MHC class II to directly activate a CD4 T cell. As such, at least two approaches have been investigated to enhance the activation of CD4 T cells. The simplest approach involves
150:
of cancer cells, it is probable that many will escape the elimination phase, and progress into the equilibrium phase. There is currently little evidence to support the existence of an equilibrium phase, aside from the observation that cancers have been shown to lie dormant, i.e. to go into
227:
Tumour antigens are those expressed by tumor cells, and recognizable as being different from self cells. Most currently classified tumor antigens are endogenously synthesized, and as such are presented on MHC class I molecules to CD8 T cells. Such antigens include products of
442:
2 mediated anti-tumor activity primarily involves recruitment of eosinophils to the tumor environment via IL-4 and IL-13. Anti-tumor eosinophil activity includes attraction of tumor-specific CTLs, activation of macrophages, and vascularization of the tumor stroma.
59:. (Burnet, 1970) More recent evidence has suggested that immunosurveillance is only part of a larger role the immune system plays in fighting cancer. Remodeling of this theory has led to the progression of the immunoediting theory, in which there are 3 phases,
232:
or tumor suppressor genes, mutants of other cellular genes, products of genes that are normally silenced, over-expressed gene products, products of oncogenic viruses, oncofetal antigens (proteins normally expressed only during development of the fetus)
1033:
Carretero, Rafael; Sektioglu, Ibrahim M.; Garbi, Natalio; Salgado, Oscar C.; Beckhove, Philipp; Hämmerling, Günter J. (2015-06-01). "Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8+ T cells".
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class I molecules, to CD8 T cells, and not expressed on the cell surface bound to MHC class II molecules, which is required for presentation to CD4 T cells. Research has shown that the two pathways by which antigens are presented cross over in the
126:
deficient mice were also shown to have a reduced ability to ward off MCA induced cancers, suggesting an important role of CD8 T cells. (Street et al. 2001) Perforin is a protein produced by CD8 T cells, which plays a central role in the
274:
reports suggest that direct recognition of tumors from tumor-antigen specific CD4 T cells might not be always beneficial. For example, it was recently shown that CD4 T cells primarily produce TNF after recognition of tumor-antigens in
673:
Haabeth, Ole Audun Werner; Tveita, Anders Aune; Fauskanger, Marte; Schjesvold, Fredrik; Lorvik, Kristina Berg; Hofgaard, Peter O.; Omholt, Hilde; Munthe, Ludvig A.; Dembic, Zlatko; Corthay, Alexandre; Bogen, Bjarne (1 January 2014).
199:(TGF-β) (Khong and Restifo, 2002) thereby suppressing the immune system, allowing for large-scale proliferation (Salazar-Onfray et al., 2007). Also, it has been observed that some cancer patients exhibit higher than normal levels of
599:
upregulation of adhesion molecules, thus extending the presentation of antigens by APC. (Chamuleau et al., 2006) A second approach involves increasing the expression of MHC class II in tumor cells. This technique has not been used
505:
17 cells can orchestrate chronic inflammatory responses, which tend to promote tumor growth and survival. In addition, some tumors have been shown to express high levels of IL-6 & TGF-β, which would reinforce a
533:
cells. Their main functions involve maintaining self-tolerance and immune homeostasis. Treg differentiation is induced by expression of FoxP3 transcription factor, and Tregs secrete a variety of immunosuppressive
1196:
Fransen, L., Van der Heyden, J., Ruysschaert, R and Fiers, W., 1986 Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell
1293:
Shankaran, V., Ikeda, H., Bruce, A.T., White, J.M., Swanson, P.E., Old, L.J. and
Schreiber, R.D., 2001. IFNγ and lymphocytes prevent primary tumor development and shape tumor immunogenicity.
258:
2005) finally, there is simply a more widespread understanding and knowledge of MHC class I tumor antigens, while MHC class II antigens remain somewhat obscure.(Pardol and
Toplain, 1998).
786:
Mailliard, Robbie B.; Egawa, Shinichi; Cai, Quan; Kalinska, Anna; Bykovskaya, Svetlana N.; Lotze, Michael T.; Kapsenberg, Martien L.; Storkus, Walter J.; Kalinski, Pawel (2002-02-18).
1265:
Qin, Z and
Blankenstein, T., 2000. CD4+ T cell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFNγ receptor expression on nonhematopoietic cells.
265:(APCs) and increased antigen presentation on MHC class I, as well as secretion of excitatory cytokines such as IL-2 (Pardol and Toplain, 1998, Kalams and Walker, 1998, Wang 2001).
654:
180:, their subsequent evasion of the immune system and their ability to be clinically detected. A number of theories have been proposed to explain this phase of the theory.
1174:
Donia, M. et al., 2015. Aberrant expression of MHC Class II in melanoma attracts inflammatory tumor specific CD4+ T cells which dampen CD8+ T cell antitumor reactivity.
638:(AML) the cells may already be MHC class II, but because of mutation, express low levels on their surface. It is believed that low levels are seen as a direct result of
1279:
Salazar-Onfray, Flavio., López, Mercedes N. and
Mendoza-Naranjo, Ariadna., 2007. Paradoxical effects of cytokines in tumor immune surveillance and tumor immune escape.
377:
1 cells are indirectly responsible for activating tumor-suppressing CTLs by activating the antigen-presenting cells which then present antigen to and activate the CTL.
578:
deficient in gp91phox, a protein involved in the production ROIs (Reactive Oxygen
Intermediates) which are also an important weapon utilized by macrophages to elicit
261:
It was believed that CD4 T cells were not involved directly in antitumour immunity, but rather functioned simply in the priming of CD8 T cells, through activation of
1286:
Shimizu, J., Yamazaki, S. and Sakaguchi, S., 1999. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity.
155:, in a person's body for years before re-emerging again in the final escape phase. It has been noted that tumors that persist in the equilibrium phase show reduced
1272:
Qiu et al., 1999 G. Qiu, J. Goodchild, R.E. Humphreys and M. Xu, Cancer immunotherapy by antisense suppression of Ii protein in MHC-class-II-positive tumor cells.
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presentation, and as such, evade an immune response. (Dunn et al., 2004) Tumor cells may, through mutations, often begin producing large quantities of inhibitory
146:
The equilibrium phase of the immunoediting theory is characterized by the continued existence of the tumour, but little growth. Due to the extremely high rate of
106:
problems can lead to cancers themselves. This experiment provides clear evidence that the immune system does, in fact, play a role in eradication of tumor cells.
737:
Akdis, Mübeccel; Burgler, Simone; Crameri, Reto; Eiwegger, Thomas; Fujita, Hiroyuki; Gomez, Enrique; Klunker, Sven; Meyer, Norbert; O'Mahony, Liam (2011-03-01).
47:
This discovery furthered the development of a previously hypothesized theory, the immunosurveillance theory. The immunosurveillance theory suggests that the
621:
technology, has yielded promising results in allowing MHC class I tumor antigens to be expressed on MHC class II molecules at the cell surface (Qui, 1999).
1167:
Chamuleau, M., Ossenkopple, G., and Loosdrecht, A., 2006. MHC class II molecules in tumor immunology: prognostic marker and target for immune modulation.
517:
17 cells have also been found to have the capacity to differentiate into IFN-γ secreting cells, thus suppressing tumor growth via IFN-γ-related pathways.
302:
were present at the site of the tumor, following vaccination, and subsequent tumour challenge. (Hung, 1998) IL-4 is the predominant cytokine produced by T
555:
result in increased presentation to T cells. (Abbas and Lichtman, 2005) It has also been shown to be involved in the expression of iNOS as well as ROIs.
109:
Further knock out experiments showed important roles of αβ T cells, γδ T cells and NK cells in tumour immunity (Girardi et al. 2001, Smyth et al., 2001)
1307:
Street, S.E., Cretney, E. and Smyth, M.J., 2001. Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis.
1300:
Smyth, M.J., Crowe, N.Y. and Godfrey, D.I., 2001. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma.
253:
T cells in antitumor immunity, rather than to CD4 T cells. This can be attributed to a number of things; CD4 T cells respond only to presentation of
384:
1 cells activates macrophages, increasing phagocytosis of pathogen and tumor cells. Activated macrophages produce IL-12, and since IL-12 promotes T
310:
1 cytokine. Earlier work has shown that these two cytokines inhibit the production of each other by inhibiting differentiation down the opposite T
102:(such as SCID mice) as an absence of these proteins does not affect DNA repair mechanisms, which becomes important when dealing with cancer, as
1314:
Street, S.E., Trapani, J.A., MacGregor, D. and Smyth, M.J., 2002. Suppression of lymphoma and epithelial malignancies effected by interferon γ.
1153:
Bui, Jack D. and Schreiber, Robert R., 2001. Cancer immunosurveillance, immunoediting and inflammation: independent or inderdependent process?
542:. Tregs are detrimental to anti-tumor immune responses, as the secretion of TGF-β and other suppressive cytokines dampens immunity from CTLs, T
586:
was responsible for inhibition of tumor induced angiogenesis and could prevent tumor growth through this method. (Qin and Blankenstein, 2000)
396:
1229:
Kalams, Spyros A. and Walker, Bruce D., 1998. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte Responses.
116:(IFNγ) showed that these mice are more likely to develop certain types of cancers as well, and suggests a role of CD4 T cells in
1189:
Dunn, Gavin P., Old, Lloyd J. and Schreiber, Robert D., 2004. The immunobiology of cancer immunosurveillance and immunoediting.
559:
196:
90:
induced tumours than were wild type mice. (Shankaran et al., 2001, Bui and Schreiber, 2007) RAG proteins are necessary for the
278:. TNF may in turn increase local immunosuppression and impair the effector functions of CD8 T cells (Donia M. et al., 2015).
1204:
Girardi, M., Oppenheim, D.E., Steele, C.R., Lewis, J.M., Glusac, E., Filler, R., Hobby, P., Sutton, B., Tigelaar, R.E. and
399:(TRAIL) pathway. NK cells produce IFN-γ and are also activated by IL-12, creating another tumor-suppressing feedback loop.
83:
1236:
Khong, H.T. and Restifo, N.P., 2002. Natural selection of tumor variants in the generation of “tumor escape” phenotypes.
94:
events necessary to produce TCRs and Igs, and as such RAG-2 deficient mice are incapable of producing functional T, B or
571:
450:
2 polarization as quantified by IL-5 production has been associated with tumor proliferation, complicating the role of T
1328:
Wang, Rong-Fu., 2001. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity.
1085:
Miyahara, Yoshihiro; Odunsi, Kunle; Chen, Wenhao; Peng, Guangyong; Matsuzaki, Junko; Wang, Rong-Fu (2008-10-07).
1342:
Xu, M., Qiu, G., Jiang, Z., Hofe, E. and Humphreys, R., 2000. Genetic modulation of tumor antigen presentation.
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and TGF-β, thereby suppressing the immune system and allowing for evasion by the tumor (Shimizu et al., 1999).
423:
2 differentiation is dependent on the presence of IL-4 and the absence of IL-12, and signature cytokines of T
51:
routinely patrols the cells of the body, and, upon recognition of a cell, or group of cells, that has become
262:
1335:
Wang, Rong-Fu., 2003. Identification of MHC class II-restricted tumor antigens recognized by CD4+ T cells.
1321:
Trinchieri, G. and Perussia, B., 1985. Immune interferon: a pleiotropic lymphokine with multiple effects.
635:
676:"How Do CD4 T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules?"
315:
1258:
Pardoll, Drew M and Toplain, Suzanne L., 1998. The role of CD4+ T cell responses in antitumor immunity.
613:
594:
Many of the aforementioned mechanisms by which CD4 cells play a role in tumor immunity are dependent on
138:
Finally, the innate immune system has also been associated with immunosurveillance (Dunn et al., 2004).
91:
1150:
Abbas, A.K, and Lichtman, 2005. A.H.Cellular and Molecular Immunology. Elsevier Saunders, Philadelphia.
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to kill infected cells. (Abbas and Lichtman, 2005) A decrease in the levels of iNOS, (as seen through
1371:
1098:
152:
1366:
1067:
953:
87:
1134:
1116:
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1007:
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885:
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212:
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As mentioned, the elimination phase is synonymous with the classic immunosurveillance theory.
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997:
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The same series of experiments, examining the role of CD4 cells, showed that high levels of
117:
113:
99:
739:"Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases"
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Hung, K et al., 1998. The central role of CD4+ T cells in the antitumor immune response.
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production. In mice deficient in IL-5, the cytokine responsible for differentiation of
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The reduction of immunity in IL-4 deficient mice, has been attributed to a decrease in
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173:
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1355:
1205:
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of the CIITA promoter genes (Morimoto et al., 2004, Chamuleau et al., 2006) and that
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479:
428:
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48:
28:
24:
19:
1087:"Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer"
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238:
1002:
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of these promoters may restore MHC class II expression (Chamuleau et al., 2006).
639:
177:
1091:
Proceedings of the National Academy of Sciences of the United States of America
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923:
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Historically, much more attention and funding has been devoted to the role of
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1011:
931:
871:
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692:
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1111:
908:"Tumor antigen-specific T helper cells in cancer immunity and immunotherapy"
848:"A cytokine-mediated link between innate immunity, inflammation, and cancer"
618:
319:
128:
32:
1138:
1063:
1019:
986:"CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful"
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889:
829:
788:"Complementary Dendritic Cell–activating Function of CD8+ and CD4+ T Cells"
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Due to the extremely polymorphic nature of MHC class II molecules, simple
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535:
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17 cell activity in the tumor microenvironment are not well understood. T
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192:
184:
161:
147:
132:
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cells that are primarily involved in promoting inflammatory responses. T
330:
299:
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1 cell differentiation, this forms a tumor-suppressing feedback loop.
55:, it will attempt to destroy them, thus preventing the growth of some
863:
563:
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1 cell anti-tumor activity is complex and includes many mechanisms. T
204:
52:
1251:
Old, L.J. and Boyse, E.A., 1964. Immunology of experimental tumors.
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responsible for the production of NO, an important molecule used by
172:
As the name implies, the escape phase is characterized by a reduced
98:. RAG-2 deficient mice were chosen over other methods of inducting
86:(Recombinase Activator Gene 2) were far less capable of preventing
187:, may actually have mutations in some of the proteins involved in
56:
23:
has grown substantially since the late 1990s. CD4 T cells (mature
617:
molecule until leaving the ER. Down regulation of this Ii, using
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1 and NK cells both contribute to killing of tumor cells via the
39:, and are important in orchestrating overall immune responses.
1160:
Burnet, F.M., 1970. The concept of immunological surveillance.
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dependent, and IFN-γ is the signature cytokine of cells of a T
250:
200:
120:, which produce large amounts of IFNγ (Street et al., 2002)
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17 polarization, creating a tumor-promoting feedback loop.
1208:, 2001. Regulation of cutaneous malignancy by γδ T cells.
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cells (Tregs) are another recently defined subset of T
131:
killing mechanisms by providing entry of degradative
726:
http://cancerres.aacrjournals.org/content/75/18/3747
655:
List of distinct cell types in the adult human body
135:into an infected cell. (Abbas and Lichtman, 2005)
164:, or 3) progression into the final escape phase.
743:The Journal of Allergy and Clinical Immunology
724:Donia M. et al., Cancer Res 2015 available at
215:actions. These T cells produce high levels of
82:In 2001, it was shown that mice deficient in
8:
984:Kim, Hye-Jung; Cantor, Harvey (2014-02-01).
906:Knutson, K. L.; Disis, M. L. (2005-08-01).
846:Lin, Wan-Wan; Karin, Michael (2007-05-01).
478:17 differentiation is induced by TGF-β and
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1001:
939:
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819:
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701:
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334:elicit their effect through eosinophils.
470:17 are a recently identified subset of T
306:2 cells, while IFNγ is the predominant T
269:Controversial role in antitumor immunity
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969:
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27:) play an important role in modulating
841:
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419:cell polarization initially defined. T
354:cell polarizations first identified. T
1281:Cytokine and Growth Factor Reviews 18
397:TNF-related apoptosis-inducing ligand
7:
1178:, doi: 10.1158/0008-5472.CAN-14-2956
792:The Journal of Experimental Medicine
43:Immunosurveillance and immunoediting
14:
852:Journal of Clinical Investigation
607:MHC class I and class II pathways
350:1 cells are one of the two main T
1260:Current Opinion in Immunology 10
1244:in haematopoietic tumour cells.
1155:Current Opinion in Immunology 19
912:Cancer Immunology, Immunotherapy
560:inducible nitric oxide synthase
521:Treg activity in tumor immunity
1274:Cancer Immunol. Immunother. 48
1199:Eur. J. Cancer Clin. Oncol. 22
590:MHC class II and immunotherapy
482:, and signature cytokines of T
462:-17 activity in tumor immunity
1:
1344:Methods in Biotechnology 18:4
1184:Proc. Natl. Acad. Sci. USA 90
1003:10.1158/2326-6066.CIR-13-0216
407:-2 activity in tumor immunity
342:-1 activity in tumor immunity
112:Another experiment involving
625:Upregulation of MHC class II
572:immunohistochemical staining
197:transforming growth factor β
454:2 cells in tumor immunity.
203:/CD25 T cells, a subset of
18:antitumor immunity role of
1393:
990:Cancer Immunology Research
756:10.1016/j.jaci.2010.11.050
1330:Trends in Immunology 22:5
1176:Cancer Res 75(18):3747-59
924:10.1007/s00262-004-0653-2
1162:Prog. Exp. Tumor Res. 13
693:10.3389/fimmu.2014.00174
263:antigen-presenting cells
1218:10.1126/science.1063916
1112:10.1073/pnas.0710686105
680:Frontiers in Immunology
415:2 cells are the other T
636:acute myeloid leukemia
427:2 cells include IL-4,
183:Cancer cells, through
1297:, pp. 1107–1111.
1290:, pp. 5211–5218.
1233:, pp. 2199–2204.
1226:, pp. 2357–2368.
1186:, pp. 3539–3543.
1182:anti-tumor immunity.
1169:Immunobiology 211:6-8
614:endoplasmic reticulum
358:1 differentiation is
16:Understanding of the
1323:Immunology Today 6:4
1240:, pp. 999–1005.
804:10.1084/jem.20011662
749:(3): 701–721.e1–70.
316:microbial infections
1318:, pp. 129–134.
1311:, pp. 192–197.
1255:, pp. 167–186.
1231:J. Exp. Med. 188:12
1212:, pp. 605–609
1201:, pp. 419–426.
1171:, pp. 616–225.
1103:2008PNAS..10515505M
1097:(40): 15505–15510.
497:The mechanisms of T
380:IFN-γ produced by T
314:pathway, in normal
245:Antitumour immunity
1346:, pp. 167–172
1339:, pp. 227–235
1332:, pp. 269–276
1325:, pp. 131–136
1304:, pp. 459–463
1283:, pp. 171–182
1276:, pp. 499–506
1269:, pp. 677–686
1262:, pp. 588–594
1253:Annu. Rev. Med. 15
1193:, pp. 137–148
1157:, pp. 203–208
211:, for their known
209:regulatory T cells
1248:pp. 844–852.
1246:Br. J. Cancer 90,
1036:Nature Immunology
486:17 cells include
213:immunosuppressive
142:Equilibrium phase
75:Elimination phase
1384:
1316:J. Exp. Med. 196
1302:Int. Immunol. 13
1224:J. Exp. Med. 188
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864:10.1172/JCI31537
858:(5): 1175–1183.
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546:cells and APCs.
114:interferon gamma
100:immunodeficiency
29:immune responses
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1288:J. Immunol. 163
1238:Nat. Immunol. 3
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504:
500:
485:
477:
473:
469:
464:
461:
453:
449:
441:
426:
422:
418:
414:
409:
406:
394:
387:
383:
376:
372:
365:
357:
353:
349:
344:
341:
313:
309:
305:
292:
289:
285:
271:
247:
225:
223:Tumour antigens
170:
144:
77:
45:
12:
11:
5:
1390:
1388:
1380:
1379:
1374:
1369:
1364:
1354:
1353:
1350:
1349:
1347:
1340:
1333:
1326:
1319:
1312:
1305:
1298:
1291:
1284:
1277:
1270:
1263:
1256:
1249:
1241:
1234:
1227:
1220:
1202:
1194:
1187:
1179:
1172:
1165:
1158:
1151:
1145:
1144:
1077:
1042:(6): 609–617.
1025:
963:
918:(8): 721–728.
895:
835:
798:(4): 473–483.
778:
729:
717:
664:
663:
661:
658:
651:
648:
626:
623:
608:
605:
591:
588:
551:
548:
543:
530:
526:
522:
519:
514:
507:
502:
498:
483:
475:
471:
467:
463:
459:
456:
451:
447:
439:
424:
420:
416:
412:
408:
404:
401:
392:
385:
381:
374:
370:
363:
355:
351:
347:
343:
339:
336:
311:
307:
303:
291:
287:
283:
280:
270:
267:
246:
243:
224:
221:
174:immunogenicity
169:
166:
157:immunogenicity
143:
140:
118:tumor immunity
76:
73:
44:
41:
25:T-helper cells
13:
10:
9:
6:
4:
3:
2:
1389:
1378:
1375:
1373:
1370:
1368:
1365:
1363:
1360:
1359:
1357:
1348:
1345:
1341:
1338:
1334:
1331:
1327:
1324:
1320:
1317:
1313:
1310:
1306:
1303:
1299:
1296:
1292:
1289:
1285:
1282:
1278:
1275:
1271:
1268:
1267:Immunity 12:6
1264:
1261:
1257:
1254:
1250:
1247:
1242:
1239:
1235:
1232:
1228:
1225:
1221:
1219:
1215:
1211:
1207:
1203:
1200:
1195:
1192:
1191:Immunity 21:2
1188:
1185:
1180:
1177:
1173:
1170:
1166:
1163:
1159:
1156:
1152:
1149:
1148:
1140:
1136:
1131:
1126:
1122:
1118:
1113:
1108:
1104:
1100:
1096:
1092:
1088:
1081:
1078:
1073:
1069:
1065:
1061:
1057:
1053:
1049:
1045:
1041:
1037:
1029:
1026:
1021:
1017:
1013:
1009:
1004:
999:
995:
991:
987:
980:
978:
976:
974:
972:
970:
968:
964:
959:
955:
951:
947:
942:
937:
933:
929:
925:
921:
917:
913:
909:
902:
900:
896:
891:
887:
882:
877:
873:
869:
865:
861:
857:
853:
849:
842:
840:
836:
831:
827:
822:
817:
813:
809:
805:
801:
797:
793:
789:
782:
779:
774:
770:
766:
762:
757:
752:
748:
744:
740:
733:
730:
727:
721:
718:
713:
709:
704:
699:
694:
689:
685:
681:
677:
669:
666:
659:
657:
656:
649:
647:
645:
644:demethylation
641:
637:
632:
624:
622:
620:
615:
606:
604:
602:
597:
589:
587:
583:
581:
577:
576:knockout mice
573:
569:
565:
561:
556:
549:
547:
541:
537:
520:
518:
511:
495:
493:
489:
481:
457:
455:
444:
436:
434:
430:
402:
400:
398:
389:
378:
367:
361:
337:
335:
332:
328:
323:
321:
317:
301:
297:
281:
279:
277:
268:
266:
264:
259:
256:
252:
244:
242:
240:
239:glycoproteins
236:
231:
222:
220:
218:
214:
210:
207:often called
206:
202:
198:
194:
190:
186:
181:
179:
175:
167:
165:
163:
158:
154:
149:
141:
139:
136:
134:
130:
125:
121:
119:
115:
110:
107:
105:
101:
97:
93:
92:recombination
89:
85:
80:
74:
72:
70:
66:
62:
58:
54:
50:
49:immune system
42:
40:
38:
34:
30:
26:
22:
21:
1343:
1337:Methods 29:3
1336:
1329:
1322:
1315:
1308:
1301:
1294:
1287:
1280:
1273:
1266:
1259:
1252:
1245:
1237:
1230:
1223:
1209:
1206:Hayday, A.C.
1198:
1190:
1183:
1175:
1168:
1161:
1154:
1094:
1090:
1080:
1039:
1035:
1028:
996:(2): 91–98.
993:
989:
915:
911:
855:
851:
795:
791:
781:
746:
742:
732:
720:
683:
679:
668:
653:
631:transfection
628:
610:
600:
596:phagocytosis
593:
584:
557:
553:
525:Regulatory T
524:
512:
496:
465:
445:
437:
410:
390:
379:
368:
345:
324:
293:
290:2 CD4T cells
272:
260:
248:
226:
182:
178:cancer cells
171:
168:Escape phase
145:
137:
122:
111:
108:
81:
78:
68:
64:
60:
46:
17:
15:
1372:Human cells
1210:Science 294
640:methylation
568:macrophages
366:1 lineage.
235:glycolipids
65:Equilibrium
61:Elimination
37:tumor cells
20:CD4 T cells
1367:Immunology
1356:Categories
1295:Nature 410
660:References
580:cell death
538:, such as
446:However, T
327:eosinophil
195:IL-10, or
104:DNA repair
1121:1091-6490
1072:205369306
1056:1529-2908
1012:2326-6074
932:0340-7004
872:0021-9738
812:0022-1007
765:1097-6825
619:antisense
536:cytokines
320:wild type
230:oncogenes
193:cytokines
153:remission
133:granzymes
129:cytotoxic
53:cancerous
33:pathogens
1309:Blood 97
1139:18832156
1064:25915731
1020:24778273
950:16010587
941:11032889
890:17476347
830:11854360
773:21377040
712:24782871
650:See also
562:) is an
276:melanoma
255:antigens
185:mutation
162:dormancy
148:mutation
124:Perforin
96:NK cells
1362:T cells
1130:2563129
1099:Bibcode
958:7644008
881:1857251
821:2193623
703:3995058
686:: 174.
601:in vivo
331:myeloid
286:1 and T
205:T cells
189:antigen
176:of the
1197:lines.
1137:
1127:
1119:
1070:
1062:
1054:
1018:
1010:
956:
948:
938:
930:
888:
878:
870:
828:
818:
810:
771:
763:
710:
700:
564:enzyme
558:iNOS (
492:IL-17F
488:IL-17A
431:, and
322:mice.
69:Escape
57:tumors
1377:Tumor
1068:S2CID
954:S2CID
550:IFN-γ
540:TGF-β
433:IL-13
360:IL-12
217:IL-10
84:RAG-2
1135:PMID
1117:ISSN
1060:PMID
1052:ISSN
1016:PMID
1008:ISSN
946:PMID
928:ISSN
886:PMID
868:ISSN
826:PMID
808:ISSN
769:PMID
761:ISSN
708:PMID
490:and
480:IL-6
429:IL-5
300:IFNγ
298:and
296:IL-4
237:and
67:and
35:and
1214:doi
1125:PMC
1107:doi
1095:105
1044:doi
998:doi
936:PMC
920:doi
876:PMC
860:doi
856:117
816:PMC
800:doi
796:195
751:doi
747:127
698:PMC
688:doi
251:CD8
201:CD4
160:of
88:MCA
31:to
1358::
1133:.
1123:.
1115:.
1105:.
1093:.
1089:.
1066:.
1058:.
1050:.
1040:16
1038:.
1014:.
1006:.
992:.
988:.
966:^
952:.
944:.
934:.
926:.
916:54
914:.
910:.
898:^
884:.
874:.
866:.
854:.
850:.
838:^
824:.
814:.
806:.
794:.
790:.
767:.
759:.
745:.
741:.
706:.
696:.
682:.
678:.
582:.
494:.
435:.
71:.
63:,
1216::
1141:.
1109::
1101::
1074:.
1046::
1022:.
1000::
994:2
960:.
922::
892:.
862::
832:.
802::
775:.
753::
714:.
690::
684:5
544:h
531:h
527:h
515:h
513:T
508:h
506:T
503:h
499:h
484:h
476:h
472:h
468:h
466:T
460:h
458:T
452:h
448:h
440:h
438:T
425:h
421:h
417:h
413:h
411:T
405:h
403:T
393:h
391:T
386:h
382:h
375:h
371:h
369:T
364:h
356:h
352:h
348:h
346:T
340:h
338:T
312:h
308:h
304:h
288:h
284:h
282:T
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