Immunity
Previews that human keratinocytes secrete IL-6 in response to Pam2Cys, and that patients with AD display increases in iNOS expressing MDSC populations in their blood and skin compared to healthy controls. However, the benefits of MDSCs in AD patients with S. aureus colonization and persistent disease are unclear. A greater understanding of the role of S. aureus and diacylated ligands for TLR2/6 heterodimers in AD progression will likely require further exploration combining more physiologically relevant animal models with mechanism targeted investigations in AD patients. The studies presented here reveal intriguing and previously unappreciated TLR2 and TLR6-dependent ‘‘Toll-erance’’ mechanisms in the skin that might be critically
important in the interrelationship between commensal bacteria and the cutaneous immune response. REFERENCES Chalmin, F., Ladoire, S., Mignot, G., Vincent, J., Bruchard, M., Remy-Martin, J.P., Boireau, W., Rouleau, A., Simon, B., Lanneau, D., et al. (2010). J. Clin. Invest. 120, 457–471. Hashimoto, M., Tawaratsumida, K., Kariya, H., Kiyohara, A., Suda, Y., Krikae, F., Kirikae, T., and Go¨tz, F. (2006). J. Immunol. 177, 3162–3169. Kaesler, S., Volz, T., Skabytska, Y., Ko¨berle, M., Hein, U., Chen, K.M., Guenova, E., Wo¨lbing, F., Ro¨cken, M., and Biedermann, T. (2014). J. Allergy Clin. Immunol. 134, 92–99. Kurokawa, K., Kim, M.S., Ichikawa, R., Ryu, K.H., Dohmae, N., Nakayama, H., and Lee, B.L. (2012). J. Bacteriol. 194, 3299–3306.
Lai, Y., Di Nardo, A., Nakatsuji, T., Leichtle, A., Yang, Y., Cogen, A.L., Wu, Z.R., Hooper, L.V., Schmidt, R.R., von Aulock, S., et al. (2009). Nat. Med. 15, 1377–1382. Pandey, S.P., Chandel, H.S., Srivastava, S., Selvaraj, S., Jha, M.K., Shukla, D., Ebensen, T., Guzman, C.A., and Saha, B. (2014). J. Immunol. 193, 3632–3643. Skabytska, Y., Wolbing, F., Gunther, C., Koberle, M., Kaesler, S., Chen, K.-M., Guenova, E., Demircioglu, D., Kempf, W., Volz, T., et al. (2014). Immunity 41, this issue, 762–775. Travers, J.B., Kozman, A., Mousdicas, N., Saha, C., Landis, M., Al-Hassani, M., Yao, W., Yao, Y., Hyatt, A.M., Sheehan, M.P., et al. (2010). J Allergy Clin Immunol 125, 146–152 e141–142. Vu, A.T., Baba, T., Chen, X., Le, T.A., Kinoshita, H., Xie, Y., Kamijo, S., Hiramatsu, K., Ikeda, S., Ogawa, H., et al. (2010). J Allergy Clinical Immunol 126, 985–993, 993 e981–983.
Tumors STING Adaptive Antitumor Immunity Vincenzo Bronte1,* 1Verona University Hospital and Department of Pathology and Diagnostics, University of Verona, 37134 Verona, Italy *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2014.11.004
Immunotherapy is revolutionizing the treatment of cancer patients, but the molecular basis for tumor immunogenicity is unclear. In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) provide evidence suggesting that dendritic cells detect DNA from tumor cells via the STING-mediated, cytosolic DNA sensing pathway. Although the terms antigenicity and immunogenicity are often used as synonyms, they refer to different features of the adaptive immune response. Antigenicity defines the capacity of an antigen to bind specifically to lymphocyte receptors, either expressed on the cell surface or when released as antibodies after B cell activation. Immunogenicity refers to the ability of an antigen to prime either T or B cells. Antigens can thus bind to a T or B cell receptor, but to be considered immunogens, they must also trigger an adaptive immune response by activating dendritic cells (DCs). In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) analyze the molecular basis for such immunogenicity, providing insight into DC activation by cancer.
While there is agreement about the existence of tumor-associated and even tumor-specific antigens, the immunogenicity of cancer is still debated. Somatic mutations in cancer can generate new antigens with a frequency varying more than 1,000-fold between the lowest and highest extremes across different cancer histology types (Lawrence et al., 2013). Melanoma has one of the highest rates of mutation and is associated with antitumor T cells in the blood or among tumor-infiltrating leukocytes in patients, as well as with serum immunoglobulin G (IgG) antibodies against hundreds of tumor antigens. Due to technical restraints, the first molecularly defined tumor-associated antigens (TAA) were shared, mostly nonmutated ‘‘self molecules,’’ but identification of immune responses specific
for epitopes generated by mutations are becoming more common. Immunogenicity, on the other hand, is both clinically and experimentally more difficult to define (Blankenstein et al., 2012). Some transplantable cell lines and tumors induced by carcinogenesis can prime the adaptive immune response, which is then able to control initially tumor growth and progressively select variants escaping immune recognition by different mechanisms (Schreiber et al., 2011). However, sporadic, autochthonous tumors can promote a response characterized by the induction of tumor-reactive IgG antibodies, the expansion of unresponsive (anergic) CD8+ T cell populations, and infiltration of T cells in neoplastic lesions (Willimsky et al., 2008). Some investigators consider this
Immunity 41, November 20, 2014 ª2014 Elsevier Inc. 679
Immunity
Previews evidence as an indication that tumors can be either immunogenic or not immunogenic, with some specific histotypes unable to generate an effective antitumor immunity. However, because generation of tumor-specific IgG requires the interplay between CD4+ T and B lymphocytes, alternative explanations might be that either some tumors elicit a prevalent humoral response or they induce anergy at either early or late time points during their progression. Despite the different views about tumor immunogenicity, it is clear that in some cancer patients there is an endogenous antitumor lymphocyte repertoire, which can be mobilized for therapy by immune modulators. Recent approval by FDA of clinical use of antibodies against checkpoint blockade molecules to treat metastatic cancer represents the long-awaited confirmation that immunotherapy is a powerful, antineoplastic treatment (Page et al., 2014). Even though clear-cut immune correlates have not been identified in patients experiencing a therapeutic benefit, it is commonly accepted that these new drugs do not act on cancer cells but rather block inhibitory signaling mediated by the T cell surface inhibitory molecules, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1). The real event that will change our views about cancer therapy and promote a fast development of new insights in immunotherapy of cancer is the clinical evidence that some patients are experiencing long-term survival, sometimes only after repeated treatments with these antibodies, which suggests but does not prove the intervention of slow rejection mechanisms proper of the adaptive immune response (Page et al., 2014). Other forms of more conventional therapies, such as chemotherapy and radiation therapy, can also influence tumor immunogenicity. Cancer cells dying after contact with antineoplastic agents either expose on their surface or release damage-associated molecular pattern molecules, such as calreticulin, ATP, and high mobility group box 1 protein, with potent stimulatory activity on DCs (Zitvogel et al., 2013). This ‘‘immunogenic cell death’’ primes T lymphocyte responses by driving enhanced phagocytosis and antigen presentation, DC maturation, activation of NLRP3-inflammasome-
dependent release of IL-1b, and TLR4and Myd88-dependent inflammatory response, with differences depending on the chemical nature of the drug (Zitvogel et al., 2013). Because a fraction of patients treated with immunotherapy does not experience clinical benefits, it is important to better understand the factors that regulate either spontaneous immunogenicity or immunogenicity induced by medical treatments (iatrogenic immunogenicity). Type I interferon (IFN), primarily comprising IFN-a and IFN-b, plays a role in both spontaneous and iatrogenic immunogenicity of tumors. Only when the type I IFN receptor 1 (IFNAR1), recognizing both IFN-a and -b, is engaged do CD8+ DCs accumulate within the tumor, crosspresent tumor antigens, and initiate an adaptive immune response dominated by CD8+ T cells, both in primary tumors and after radiation therapy. Building on these already published data, in this issue of Immunity, Deng et al. and Woo et al. link sensing of tumor-cell derived DNA by the STING-mediated cytosolic DNA sensing pathway to type I IFN production in both spontaneous and iatrogenic cancer immunogenicity. STING is a signaling molecule in the innate response to cytosolic nucleic acid ligands. Cytosolic detection of DNA by cGAMP synthase (cGAS) catalyzes the generation of 20 to 50 cyclic GMP-AMP (cGAMP), which binds to STING allowing it to recruit, phosphorylate, and activate TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Within the nucleus, IRF3 initiates a transcriptional program leading to production of type I IFN that, once released by DCs, binds to its receptor, acting in autocrine and paracrine fashion. Type I IFN-stimulated DCs cross-present TAA and activate tumor-specific CD8+ T lymphocytes (Figure 1). These results have a potential translational impact. In fact, interference with lymphocyte inhibitory pathways, such as CTLA-4 and PD-L1-PD-1, was therapeutically ineffective in mice lacking STING, indicating that STING pathway is also important for checkpoint blockade therapies (Woo et al., 2014). Moreover, the STING activator cGAMP was unsuccessful alone but synergized with radiation to decrease tumor burden and increase survival in wild-type but not STING-deficient
680 Immunity 41, November 20, 2014 ª2014 Elsevier Inc.
mice, designating cGAMP as a prospective drug to decrease tumor resistance to radiation (Deng et al., 2014). To complete the picture, it must be pointed out that type I IFN can be also released by tumor cells exposed to anthracyclines, which activate a circuit leading to RNA recognition by TLR3 within the same tumor cells, release of type I IFN, and downstream production of the chemokine CxCL10 (Sistigu et al., 2014). Thus, the autocrine and paracrine activity of IFN also contributes to in vivo chemotherapy mechanism of action by activating the adaptive immunity (Sistigu et al., 2014). These studies by Deng et al. and Woo et al. raise several unanswered questions. It appears that cancer cell DNA itself is not more immunogenic than DNA from noncancerous cells, as similar amounts of IFN-b were produced after transfection of DCs with DNA isolated from normal splenocytes, provided that the DNA is mixed with liposomes to allow delivery to the cytosol (Woo et al., 2014). However, injection of splenocytes in the subcutaneous space is not sufficient to activate the STING-dependent cascade (Woo et al., 2014), indicating that cell death due to experimental protocols is not the contributing factor and some unknown features related to neoplastic cell transformation and demise are instead essential. Moreover, it is also unclear how DNA is gaining access to DC cytosol. Although some evidence is presented for the role of phagocytic activity after radiation therapy (Deng et al., 2014), how DNA is transferred from untreated tumor cells to DCs remains a mystery. How can tumors, either spontaneously or in response to therapy, overcome the tolerance circuits that normally restrain the innate response to nucleic acids? Studies of autoimmune diseases, in which continuous triggering of immune responses to self-antigens can sustain severe tissue destruction, might provide some clues. Systemic lupus erythematous (SLE) is an autoimmune disease characterized by the presence of pathogenic autoantibodies recognizing double-stranded DNA and small nuclear ribonucleoproteins. Type I interferon, released by plasmocytoid DCs, plays a central role in SLE pathogenesis by fueling self-sustaining loops that progressively hamper peripheral immune
Immunity
Previews by interference with checkpoint blockade pathways. ACKNOWLEDGMENTS This work was supported by grants from the Italian Ministry of Health; Italian Ministry of Education (FIRB cup: B31J11000420001), Universities, and Research; Italian Association for Cancer Research (AIRC, grants 6599, 12182, and 14103). REFERENCES Blankenstein, T., Coulie, P.G., Gilboa, E., and Jaffee, E.M. (2012). Nat. Rev. Cancer 12, 307–313. Crow, M.K. (2014). J. Immunol. 192, 5459–5468. Deng, L., Liang, H., Xu, M., Yang, X., Burnette, B., Arina, A., Li, X.-D., Mauceri, H., Beckett, M., Darga, T., et al. (2014). Immunity 41, this issue, 843–852. Gehrke, N., Mertens, C., Zillinger, T., Wenzel, J., Bald, T., Zahn, S., Tu¨ting, T., Hartmann, G., and Barchet, W. (2013). Immunity 39, 482–495.
Figure 1. Spontaneous and Iatrogenic Tumor Immunogenicity Require STING and Type I IFN After tumor implantation or radiation therapy, tumor-derived DNA can access the DC cytosol and bind cGAS to activate STING-mediated Ifnb transcription. 20 30 cGAMP is generated by cGAS from the substrates ATP and GTP and, in turn, binds to and activates STING dimers, inducing phosphorylation of TBK-1 and IRF3. Nuclear translocation of phosphorylated IRF3 controls IFN-b transcription. After binding to its receptor, IFN-b renders DCs competent to present tumor antigens and prime CD8+ T lymphocytes.
tolerance and maintain disease activity (Crow, 2014). However, type I IFN cooperates with other immune mechanisms, such as impaired clearance of immune complexes and apoptotic material due to defect in complement proteins. Moreover, subtle DNA modifications could be required to increase DNA immunogenicity. In fact, oxidized DNA generated by cellular oxidative damage is protected from 30 repair exonuclease 1-mediated degradation and thus more prone to activate STING pathway in SLE (Gehrke
et al., 2013). Defining better the molecular elements that contribute to sustained activation of innate and adaptive immunity by DNA in the context of autoimmunity might provide insight into innate immune sensing pathways in the context of cancer immunity. These findings might also help to enlarge the fraction of patients who respond to immunotherapy with prolonged control of the tumor. Indeed, enhancing the immunogenicity of their cancers might expand the lymphocyte repertoire that is then unleashed
Lawrence, M.S., Stojanov, P., Polak, P., Kryukov, G.V., Cibulskis, K., Sivachenko, A., Carter, S.L., Stewart, C., Mermel, C.H., Roberts, S.A., et al. (2013). Nature 499, 214–218. Page, D.B., Postow, M.A., Callahan, M.K., Allison, J.P., and Wolchok, J.D. (2014). Annu. Rev. Med. 65, 185–202. Schreiber, R.D., Old, L.J., and Smyth, M.J. (2011). Science 331, 1565–1570. Sistigu, A., Yamazaki, T., Vacchelli, E., Chaba, K., Enot, D.P., Adam, J., Vitale, I., Goubar, A., Baracco, E.E., Reme´dios, C., et al. (2014). Nat. Med. http://dx.doi.org/10.1038/nm.3708, October 26, 2014. Willimsky, G., Cze´h, M., Loddenkemper, C., Gellermann, J., Schmidt, K., Wust, P., Stein, H., and Blankenstein, T. (2008). J. Exp. Med. 205, 1687–1700. Woo, E.Y., Fuertes, M.B., Corrales, L., Spranger, S., Furdyna, M.J., Leung, M.Y.K., Duggan, R., Wang, Y., Barber, G.N., Fitzgerald, K.A., et al. (2014). Immunity 41, this issue, 830–842. Zitvogel, L., Galluzzi, L., Smyth, M.J., and Kroemer, G. (2013). Immunity 39, 74–88.
Immunity 41, November 20, 2014 ª2014 Elsevier Inc. 681
Previews that human keratinocytes secrete IL-6 in response to Pam2Cys, and that patients with AD display increases in iNOS expressing MDSC populations in their blood and skin compared to healthy controls. However, the benefits of MDSCs in AD patients with S. aureus colonization and persistent disease are unclear. A greater understanding of the role of S. aureus and diacylated ligands for TLR2/6 heterodimers in AD progression will likely require further exploration combining more physiologically relevant animal models with mechanism targeted investigations in AD patients. The studies presented here reveal intriguing and previously unappreciated TLR2 and TLR6-dependent ‘‘Toll-erance’’ mechanisms in the skin that might be critically
important in the interrelationship between commensal bacteria and the cutaneous immune response. REFERENCES Chalmin, F., Ladoire, S., Mignot, G., Vincent, J., Bruchard, M., Remy-Martin, J.P., Boireau, W., Rouleau, A., Simon, B., Lanneau, D., et al. (2010). J. Clin. Invest. 120, 457–471. Hashimoto, M., Tawaratsumida, K., Kariya, H., Kiyohara, A., Suda, Y., Krikae, F., Kirikae, T., and Go¨tz, F. (2006). J. Immunol. 177, 3162–3169. Kaesler, S., Volz, T., Skabytska, Y., Ko¨berle, M., Hein, U., Chen, K.M., Guenova, E., Wo¨lbing, F., Ro¨cken, M., and Biedermann, T. (2014). J. Allergy Clin. Immunol. 134, 92–99. Kurokawa, K., Kim, M.S., Ichikawa, R., Ryu, K.H., Dohmae, N., Nakayama, H., and Lee, B.L. (2012). J. Bacteriol. 194, 3299–3306.
Lai, Y., Di Nardo, A., Nakatsuji, T., Leichtle, A., Yang, Y., Cogen, A.L., Wu, Z.R., Hooper, L.V., Schmidt, R.R., von Aulock, S., et al. (2009). Nat. Med. 15, 1377–1382. Pandey, S.P., Chandel, H.S., Srivastava, S., Selvaraj, S., Jha, M.K., Shukla, D., Ebensen, T., Guzman, C.A., and Saha, B. (2014). J. Immunol. 193, 3632–3643. Skabytska, Y., Wolbing, F., Gunther, C., Koberle, M., Kaesler, S., Chen, K.-M., Guenova, E., Demircioglu, D., Kempf, W., Volz, T., et al. (2014). Immunity 41, this issue, 762–775. Travers, J.B., Kozman, A., Mousdicas, N., Saha, C., Landis, M., Al-Hassani, M., Yao, W., Yao, Y., Hyatt, A.M., Sheehan, M.P., et al. (2010). J Allergy Clin Immunol 125, 146–152 e141–142. Vu, A.T., Baba, T., Chen, X., Le, T.A., Kinoshita, H., Xie, Y., Kamijo, S., Hiramatsu, K., Ikeda, S., Ogawa, H., et al. (2010). J Allergy Clinical Immunol 126, 985–993, 993 e981–983.
Tumors STING Adaptive Antitumor Immunity Vincenzo Bronte1,* 1Verona University Hospital and Department of Pathology and Diagnostics, University of Verona, 37134 Verona, Italy *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2014.11.004
Immunotherapy is revolutionizing the treatment of cancer patients, but the molecular basis for tumor immunogenicity is unclear. In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) provide evidence suggesting that dendritic cells detect DNA from tumor cells via the STING-mediated, cytosolic DNA sensing pathway. Although the terms antigenicity and immunogenicity are often used as synonyms, they refer to different features of the adaptive immune response. Antigenicity defines the capacity of an antigen to bind specifically to lymphocyte receptors, either expressed on the cell surface or when released as antibodies after B cell activation. Immunogenicity refers to the ability of an antigen to prime either T or B cells. Antigens can thus bind to a T or B cell receptor, but to be considered immunogens, they must also trigger an adaptive immune response by activating dendritic cells (DCs). In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) analyze the molecular basis for such immunogenicity, providing insight into DC activation by cancer.
While there is agreement about the existence of tumor-associated and even tumor-specific antigens, the immunogenicity of cancer is still debated. Somatic mutations in cancer can generate new antigens with a frequency varying more than 1,000-fold between the lowest and highest extremes across different cancer histology types (Lawrence et al., 2013). Melanoma has one of the highest rates of mutation and is associated with antitumor T cells in the blood or among tumor-infiltrating leukocytes in patients, as well as with serum immunoglobulin G (IgG) antibodies against hundreds of tumor antigens. Due to technical restraints, the first molecularly defined tumor-associated antigens (TAA) were shared, mostly nonmutated ‘‘self molecules,’’ but identification of immune responses specific
for epitopes generated by mutations are becoming more common. Immunogenicity, on the other hand, is both clinically and experimentally more difficult to define (Blankenstein et al., 2012). Some transplantable cell lines and tumors induced by carcinogenesis can prime the adaptive immune response, which is then able to control initially tumor growth and progressively select variants escaping immune recognition by different mechanisms (Schreiber et al., 2011). However, sporadic, autochthonous tumors can promote a response characterized by the induction of tumor-reactive IgG antibodies, the expansion of unresponsive (anergic) CD8+ T cell populations, and infiltration of T cells in neoplastic lesions (Willimsky et al., 2008). Some investigators consider this
Immunity 41, November 20, 2014 ª2014 Elsevier Inc. 679
Immunity
Previews evidence as an indication that tumors can be either immunogenic or not immunogenic, with some specific histotypes unable to generate an effective antitumor immunity. However, because generation of tumor-specific IgG requires the interplay between CD4+ T and B lymphocytes, alternative explanations might be that either some tumors elicit a prevalent humoral response or they induce anergy at either early or late time points during their progression. Despite the different views about tumor immunogenicity, it is clear that in some cancer patients there is an endogenous antitumor lymphocyte repertoire, which can be mobilized for therapy by immune modulators. Recent approval by FDA of clinical use of antibodies against checkpoint blockade molecules to treat metastatic cancer represents the long-awaited confirmation that immunotherapy is a powerful, antineoplastic treatment (Page et al., 2014). Even though clear-cut immune correlates have not been identified in patients experiencing a therapeutic benefit, it is commonly accepted that these new drugs do not act on cancer cells but rather block inhibitory signaling mediated by the T cell surface inhibitory molecules, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1). The real event that will change our views about cancer therapy and promote a fast development of new insights in immunotherapy of cancer is the clinical evidence that some patients are experiencing long-term survival, sometimes only after repeated treatments with these antibodies, which suggests but does not prove the intervention of slow rejection mechanisms proper of the adaptive immune response (Page et al., 2014). Other forms of more conventional therapies, such as chemotherapy and radiation therapy, can also influence tumor immunogenicity. Cancer cells dying after contact with antineoplastic agents either expose on their surface or release damage-associated molecular pattern molecules, such as calreticulin, ATP, and high mobility group box 1 protein, with potent stimulatory activity on DCs (Zitvogel et al., 2013). This ‘‘immunogenic cell death’’ primes T lymphocyte responses by driving enhanced phagocytosis and antigen presentation, DC maturation, activation of NLRP3-inflammasome-
dependent release of IL-1b, and TLR4and Myd88-dependent inflammatory response, with differences depending on the chemical nature of the drug (Zitvogel et al., 2013). Because a fraction of patients treated with immunotherapy does not experience clinical benefits, it is important to better understand the factors that regulate either spontaneous immunogenicity or immunogenicity induced by medical treatments (iatrogenic immunogenicity). Type I interferon (IFN), primarily comprising IFN-a and IFN-b, plays a role in both spontaneous and iatrogenic immunogenicity of tumors. Only when the type I IFN receptor 1 (IFNAR1), recognizing both IFN-a and -b, is engaged do CD8+ DCs accumulate within the tumor, crosspresent tumor antigens, and initiate an adaptive immune response dominated by CD8+ T cells, both in primary tumors and after radiation therapy. Building on these already published data, in this issue of Immunity, Deng et al. and Woo et al. link sensing of tumor-cell derived DNA by the STING-mediated cytosolic DNA sensing pathway to type I IFN production in both spontaneous and iatrogenic cancer immunogenicity. STING is a signaling molecule in the innate response to cytosolic nucleic acid ligands. Cytosolic detection of DNA by cGAMP synthase (cGAS) catalyzes the generation of 20 to 50 cyclic GMP-AMP (cGAMP), which binds to STING allowing it to recruit, phosphorylate, and activate TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Within the nucleus, IRF3 initiates a transcriptional program leading to production of type I IFN that, once released by DCs, binds to its receptor, acting in autocrine and paracrine fashion. Type I IFN-stimulated DCs cross-present TAA and activate tumor-specific CD8+ T lymphocytes (Figure 1). These results have a potential translational impact. In fact, interference with lymphocyte inhibitory pathways, such as CTLA-4 and PD-L1-PD-1, was therapeutically ineffective in mice lacking STING, indicating that STING pathway is also important for checkpoint blockade therapies (Woo et al., 2014). Moreover, the STING activator cGAMP was unsuccessful alone but synergized with radiation to decrease tumor burden and increase survival in wild-type but not STING-deficient
680 Immunity 41, November 20, 2014 ª2014 Elsevier Inc.
mice, designating cGAMP as a prospective drug to decrease tumor resistance to radiation (Deng et al., 2014). To complete the picture, it must be pointed out that type I IFN can be also released by tumor cells exposed to anthracyclines, which activate a circuit leading to RNA recognition by TLR3 within the same tumor cells, release of type I IFN, and downstream production of the chemokine CxCL10 (Sistigu et al., 2014). Thus, the autocrine and paracrine activity of IFN also contributes to in vivo chemotherapy mechanism of action by activating the adaptive immunity (Sistigu et al., 2014). These studies by Deng et al. and Woo et al. raise several unanswered questions. It appears that cancer cell DNA itself is not more immunogenic than DNA from noncancerous cells, as similar amounts of IFN-b were produced after transfection of DCs with DNA isolated from normal splenocytes, provided that the DNA is mixed with liposomes to allow delivery to the cytosol (Woo et al., 2014). However, injection of splenocytes in the subcutaneous space is not sufficient to activate the STING-dependent cascade (Woo et al., 2014), indicating that cell death due to experimental protocols is not the contributing factor and some unknown features related to neoplastic cell transformation and demise are instead essential. Moreover, it is also unclear how DNA is gaining access to DC cytosol. Although some evidence is presented for the role of phagocytic activity after radiation therapy (Deng et al., 2014), how DNA is transferred from untreated tumor cells to DCs remains a mystery. How can tumors, either spontaneously or in response to therapy, overcome the tolerance circuits that normally restrain the innate response to nucleic acids? Studies of autoimmune diseases, in which continuous triggering of immune responses to self-antigens can sustain severe tissue destruction, might provide some clues. Systemic lupus erythematous (SLE) is an autoimmune disease characterized by the presence of pathogenic autoantibodies recognizing double-stranded DNA and small nuclear ribonucleoproteins. Type I interferon, released by plasmocytoid DCs, plays a central role in SLE pathogenesis by fueling self-sustaining loops that progressively hamper peripheral immune
Immunity
Previews by interference with checkpoint blockade pathways. ACKNOWLEDGMENTS This work was supported by grants from the Italian Ministry of Health; Italian Ministry of Education (FIRB cup: B31J11000420001), Universities, and Research; Italian Association for Cancer Research (AIRC, grants 6599, 12182, and 14103). REFERENCES Blankenstein, T., Coulie, P.G., Gilboa, E., and Jaffee, E.M. (2012). Nat. Rev. Cancer 12, 307–313. Crow, M.K. (2014). J. Immunol. 192, 5459–5468. Deng, L., Liang, H., Xu, M., Yang, X., Burnette, B., Arina, A., Li, X.-D., Mauceri, H., Beckett, M., Darga, T., et al. (2014). Immunity 41, this issue, 843–852. Gehrke, N., Mertens, C., Zillinger, T., Wenzel, J., Bald, T., Zahn, S., Tu¨ting, T., Hartmann, G., and Barchet, W. (2013). Immunity 39, 482–495.
Figure 1. Spontaneous and Iatrogenic Tumor Immunogenicity Require STING and Type I IFN After tumor implantation or radiation therapy, tumor-derived DNA can access the DC cytosol and bind cGAS to activate STING-mediated Ifnb transcription. 20 30 cGAMP is generated by cGAS from the substrates ATP and GTP and, in turn, binds to and activates STING dimers, inducing phosphorylation of TBK-1 and IRF3. Nuclear translocation of phosphorylated IRF3 controls IFN-b transcription. After binding to its receptor, IFN-b renders DCs competent to present tumor antigens and prime CD8+ T lymphocytes.
tolerance and maintain disease activity (Crow, 2014). However, type I IFN cooperates with other immune mechanisms, such as impaired clearance of immune complexes and apoptotic material due to defect in complement proteins. Moreover, subtle DNA modifications could be required to increase DNA immunogenicity. In fact, oxidized DNA generated by cellular oxidative damage is protected from 30 repair exonuclease 1-mediated degradation and thus more prone to activate STING pathway in SLE (Gehrke
et al., 2013). Defining better the molecular elements that contribute to sustained activation of innate and adaptive immunity by DNA in the context of autoimmunity might provide insight into innate immune sensing pathways in the context of cancer immunity. These findings might also help to enlarge the fraction of patients who respond to immunotherapy with prolonged control of the tumor. Indeed, enhancing the immunogenicity of their cancers might expand the lymphocyte repertoire that is then unleashed
Lawrence, M.S., Stojanov, P., Polak, P., Kryukov, G.V., Cibulskis, K., Sivachenko, A., Carter, S.L., Stewart, C., Mermel, C.H., Roberts, S.A., et al. (2013). Nature 499, 214–218. Page, D.B., Postow, M.A., Callahan, M.K., Allison, J.P., and Wolchok, J.D. (2014). Annu. Rev. Med. 65, 185–202. Schreiber, R.D., Old, L.J., and Smyth, M.J. (2011). Science 331, 1565–1570. Sistigu, A., Yamazaki, T., Vacchelli, E., Chaba, K., Enot, D.P., Adam, J., Vitale, I., Goubar, A., Baracco, E.E., Reme´dios, C., et al. (2014). Nat. Med. http://dx.doi.org/10.1038/nm.3708, October 26, 2014. Willimsky, G., Cze´h, M., Loddenkemper, C., Gellermann, J., Schmidt, K., Wust, P., Stein, H., and Blankenstein, T. (2008). J. Exp. Med. 205, 1687–1700. Woo, E.Y., Fuertes, M.B., Corrales, L., Spranger, S., Furdyna, M.J., Leung, M.Y.K., Duggan, R., Wang, Y., Barber, G.N., Fitzgerald, K.A., et al. (2014). Immunity 41, this issue, 830–842. Zitvogel, L., Galluzzi, L., Smyth, M.J., and Kroemer, G. (2013). Immunity 39, 74–88.
Immunity 41, November 20, 2014 ª2014 Elsevier Inc. 681
