Investigations of endogenous antitumor responses have unveiled a previously unappreciated complexity of interaction among tumor cells, stroma, and immune elements. Innate immune activation by stress-inducible signals on tumor cells triggers a response aimed at controlling disease development; effective responses may transition to adaptive immunity that manifests further specificity and memory. However, persistent immune activation may also result in an interplay of innate and adaptive elements that supports tumor cell proliferation, survival, invasion, angiogenesis, and metastasis. A central player that has emerged in coordinating these tumor-promoting inflammatory responses is the NF-kB transcription factor (Karin, 2006). A more detailed understanding of the mechanisms regulating the development of tumor-protective or tumor-promoting host responses is critical to the crafting of immunotherapeutic strategies.


Akbari, O., Faul, J. L., Hoyte, E. G., Berry, G. J., Wahlstrom, J., Kronenberg, M., DeKruyff, R. H., and Umetsu, D. T. (2006). CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 1117-1129. Boon, T., and van der Bruggen, P. (1996). Human tumor antigens recognized by T lymphocytes. J. Exp. Med. 183, 725-729. Brandes, M., Willimann, K., and Moser, B. (2005). Professional antigen-presentation function by human gammadelta T Cells. Science 309, 264-268.

Chan, C. W., Crafton, E., Fan, H. N., Flook, J., Yoshimura, K., Skarica, M., Brockstedt, D., Duben-sky, T. W., Stins, M. F., Lanier, L. L., et al. (2006). Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat. Med. 12, 207-213.

Clark, W., Elder, D., Guerry, D., Braitman, L., Trock, B., Schultz, D., Synnestvedt, M., and Halpern, A. (1989). Model predicting survival in stage I melanoma based on tumor progression. J. Natl. Cancer Inst. 81, 1893-1904.

Colombo, M. P., Ferrari, G., Stoppacciaro, A., Parenza, M., Rodolfo, M., Mavillo, F., and Parmiani, G. (1991). Granulocyte-colony stimulating factor gene suppresses tumorigenicity of a murine adenocarci-noma in vivo. J. Exp. Med. 173, 889-897.

Condeelis, J., and Pollard, J. W. (2006). Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263-266.

Crowe, N. Y., Coquet, J. M., Berzins, S. P., Kyparis-soudis, K., Keating, R., Pellicci, D. G., Hayakawa, Y., Godfrey, D. I., and Smyth, M. J. (2005). Differential antitumor immunity mediated by NKT cell subsets in vivo. J. Exp. Med. 202, 1279-1288.

Cui, J., Shin, T., Kawano, T., Sato, H., Kondo, E., Toura, I., Kaneko, Y., Koseki, H., Kanno, M., and Taniguchi, M. (1997). Requirement for Va14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623-1626.

Curcio, C., Di Carlo, E., Clynes, R., Smyth, M. J., Boggio, K., Quaglino, E., Spadaro, M., Colombo, M. P., Amici, A., Lollini, P. L., et al. (2003). Nonredundant roles of antibody, cytokines, and perforin in the eradication of established Her-2/neu carcinomas. J. Clin. Invest. 111, 1161-1170.

Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J. R., Zhang, L., Burow, M., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942-949.

Daniel, D., Meyer-Morse, N., Bergsland, E. K., Dehne, K., Coussens, L. M., and Hanahan, D. (2003). Immune enhancement of skin carcinogenesis by CD4+ T cells. J. Exp. Med. 197, 1017-1028.

Davidson, W., Giese, T., and Fredrickson, T. (1998). Spontaneous development of plasmacytoid tumors in mice with defective fas-fas ligand interactions. J. Exp. Med. 187, 1825-1838.

de Visser, K. E., Korets, L. V., and Coussens, L. M. (2005). De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411-423.

Dhodapkar, K. M., Krasovsky, J., Williamson, B., and Dhodapkar, M. V. (2002). Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J. Exp. Med. 195, 125-133.

Dranoff, G. (2004). Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11-22.

Dranoff, G. (2005). The therapeutic implications of intratumoral regulatory T cells. Clin. Cancer Res. 11, 8226-8229.

Dunn, G. P., Bruce, A. T., Sheehan, K. C., Shankaran, V., Uppaluri, R., Bui, J. D., Diamond, M. S., Koebel, C. M., Arthur, C., White, J. M., and Schreiber, R. D. (2005). A critical function for type I interferons in cancer immunoediting. Nat. Immunol. 6, 722-729.

Dunn, G. P., Old, L. J., and Schreiber, R. D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137-148.

Enzler, T., Gillessen, S., Manis, J. P., Ferguson, D., Fleming, J., Alt, F. W., Mihm, M., and Dranoff, G. (2003). Deficiencies of GM-CSF and interferon-gamma link inflammation and cancer. J. Exp. Med. 197, 1213-1219.

Erdman, S. E., Sohn, J. J., Rao, V. P., Nambiar, P. R., Ge, Z., Fox, J. G., and Schauer, D. B. (2005). CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res. 65, 3998-4004.

Fehniger, T., Suzuki, K., Ponnappan, A., VanDeusen, J., Cooper, M., Florea, S., Freud, A., Robinson, M., Durbin, J., and Caligiuri, M. (2001). Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory pheno-type CD8+ T cells. J. Exp. Med. 193, 219-231.

Gabrilovich, D. (2004). Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat. Rev. Immunol. 4, 941-952.

Gasser, S., Orsulic, S., Brown, E. J., and Raulet, D. H. (2005). The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186-1190.

Gazit, R., Gruda, R., Elboim, M., Arnon, T. I., Katz, G., Achdout, H., Hanna, J., Qimron, U., Landau, G., Greenbaum, E., et al. (2006). Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat. Immunol. 7, 517-523.

Gillessen, S., Naumov, Y. N., Nieuwenhuis, E. E., Exley, M. A., Lee, F. S., Mach, N., Luster, A. D., Blumberg, R. S., Taniguchi, M., Balk, S. P., et al. (2003). CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion. Proc. Natl. Acad. Sci. USA 100, 8874-8879.

Girardi, M., Glusac, E., Filler, R. B., Roberts, S. J., Propperova, I., Lewis, J., Tigelaar, R. E., and Hayday, A. C. (2003). The distinct contributions of murine T cell receptor (TCR)gammadelta+ and TCRalpha-beta+ T cells to different stages of chemically induced skin cancer. J. Exp. Med. 198, 747-755.

Hanada, K., Yewdell, J. W., and Yang, J. C. (2004). Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427, 252-256.

Hayday, A. C. (2000). Gamma-delta cells: A right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18, 975-1026.

Hicks, A. M., Riedlinger, G., Willingham, M. C., Alexander-Miller, M. A., Von Kap-Herr, C., Pette-nati, M. J., Sanders, A. M., Weir, H. M., Du, W., Kim, J., et al. (2006). Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc. Natl. Acad. Sci. USA 103, 7753-7758.

Hodi, F. S., and Dranoff, G. (2006). Combinatorial cancer immunotherapy. Adv. Immunol. 90, 337360.

Hung, K., Hayashi, R., Lafond-Walker, A., Lowenstein, C., Pardoll, H., and Levitsky, H. (1998). The central role of CD4+ T cells in the antitumor immune response. J. Exp. Med. 188, 2357-2368.

Karin, M. (2006). NF-kappaB and cancer: Mechanisms and targets. Mol. Carcinog. 45, 355-361.

Langowski, J. L., Zhang, X., Wu, L., Mattson, J. D., Chen, T., Smith, K., Basham, B., McClanahan, T., Kastelein, R. A., and Oft, M. (2006). IL-23 promotes tumour incidence and growth. Nature 442, 461465.

Matzinger, P. (2002). The danger model: A renewed sense of self. Science 296, 301-305.

Medzhitov, R. (2001). Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135-145.

Nakamoto, Y., Guidotti, L. G., Kuhlen, C. V., Fowler, P., and Chisari, F. V. (1998). Immune pathogenesis of hepatocellular carcinoma. J. Exp. Med. 188, 341350.

Nimmerjahn, F., and Ravetch, J. V. (2005). Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science 310, 1510-1512.

Nishikawa, H., Kato, T., Tawara, I., Saito, K., Ikeda, H., Kuribayashi, K., Allen, P. M., Schreiber, R. D., Sakaguchi, S., Old, L. J., and Shiku, H. (2005). Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells. J. Exp. Med. 201, 681-686.

Oppenheim, D. E., Roberts, S. J., Clarke, S. L., Filler, R., Lewis, J. M., Tigelaar, R. E., Girardi, M., and Hayday, A. C. (2005). Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat. Immunol. 6, 928937.

Pages, F., Berger, A., Camus, M., Sanchez-Cabo, F., Costes, A., Molidor, R., Mlecnik, B., Kirilovsky, A., Nilsson, M., Damotte, D., et al. (2005). Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654-2666.

Parrish-Novak, J., Dillon, S. R., Nelson, A., Hammond, A., Sprecher, C., Gross, J. A., Johnston, J., Madden, K., Xu, W., West, J., et al. (2000). Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 5763.

Raulet, D. H. (2003). Roles of the NKG2D immunore-ceptor and its ligands. Nat. Rev. Immunol. 3, 781790.

Rosenberg, S. A. (2001). Progress in human tumour immunology and immunotherapy. Nature 411, 380384.

Shankaran, V., Ikeda, H., Bruce, A. T., White, J. M., Swanson, P. E., Old, L. J., and Schreiber, R. D. (2001). IFNg and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107-1111.

Smyth, M., Thia, K., Street, S., Cretney, E., Trapani, J., Taniguchi, M., Kawano, T., Pelikan, S., Crowe, N., and Godfrey, D. (2000a). Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661-668.

Smyth, M., Thia, K., Street, S., MacGregor, D., Godfrey,

D., and Trapani, J. (2000b). Perforin-mediated cyto-toxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 192, 755-760.

Smyth, M. J., Cretney, E., Takeda, K., Wiltrout, R. H., Sedger, L. M., Kayagaki, N., Yagita, H., and Okumura, K. (2001). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J. Exp. Med. 193, 661-670.

Smyth, M. J., Swann, J., Cretney, E., Zerafa, N., Yokoyama, W. M., and Hayakawa, Y. (2005). NKG2D function protects the host from tumor initiation. J. Exp. Med. 202, 583-588.

Taieb, J., Chaput, N., Menard, C., Apetoh, L., Ullrich,

E., Bonmort, M., Pequignot, M., Casares, N., Terme, M., Flament, C., et al. (2006). A novel dendritic cell subset involved in tumor immunosurveillance. Nat. Med. 12, 214-219.

Takaoka, A., Hayakawa, S., Yanai, H., Stoiber, D., Negishi, H., Kikuchi, H., Sasaki, S., Imai, K., Shibue, T., Honda, K., and Taniguchi, T. (2003). Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence. Nature 424, 516-523.

Takeda, K., Smyth, M. J., Cretney, E., Hayakawa, Y., Kayagaki, N., Yagita, H., and Okumura, K. (2002).

Critical role for tumor necrosis factor-related apop-tosis-inducing ligand in immune surveillance against tumor development. J. Exp. Med. 195, 161169.

Taniguchi, M., Harada, M., Kojo, S., Nakayama, T., and Wakao, H. (2003). The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu. Rev. Immunol. 21, 483-513.

Teague, R. M., Sather, B. D., Sacks, J. A., Huang, M. Z., Dossett, M. L., Morimoto, J., Tan, X., Sutton, S. E., Cooke, M. P., Ohlen, C., and Greenberg, P. D. (2006). Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat. Med. 12, 335-341.

Terabe, M., Matsui, S., Park, J. M., Mamura, M., Noben-Trauth, N., Donaldson, D. D., Chen, W., Wahl, S. M., Ledbetter, S., Pratt, B., et al. (2003). Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: Abrogation prevents tumor recurrence. J. Exp. Med. 198, 17411752.

Vigneron, N., Stroobant, V., Chapiro, J., Ooms, A., Degiovanni, G., Morel, S., van der Bruggen, P., Boon, T., and Van den Eynde, B. J. (2004). An antigenic peptide produced by peptide splicing in the protea-some. Science 304, 587-590.

Wang, H. Y., Lee, D. A., Peng, G., Guo, Z., Li, Y., Kiniwa, Y., Shevach, E. M., and Wang, R. F. (2004). Tumor-specific human CD4+ regulatory T cells and their ligands: Implications for immunotherapy. Immunity 20, 107-118.

Yu, P., Lee, Y., Liu, W., Chin, R. K., Wang, J., Wang, Y., Schietinger, A., Philip, M., Schreiber, H., and Fu, Y. X. (2004). Priming of naive T cells inside tumors leads to eradication of established tumors. Nat. Immunol. 5, 141-149.

Zhang, L., Conejo-Garcia, J., Katsaros, D., Gimotty, P., Massobrio, M., Regnani, G., Makrigiannakis, A., Gray, H., Schlienger, K., Liebman, M., et al. (2003). Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203213.

This page intentionally left blank

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

Get My Free Ebook

Post a comment