OncoImmunology
ISSN: (Print) 2162-402X (Online) Journal homepage: http://www.tandfonline.com/loi/koni20
Unleashing antitumor T-cell activation without ensuing autoimmunity: the case for A20-deletion + in adoptive CD8 T-cell therapy Grégory Verdeil & Anne-Marie Schmitt-Verhulst To cite this article: Grégory Verdeil & Anne-Marie Schmitt-Verhulst (2014) Unleashing antitumor T-cell activation without ensuing autoimmunity: the case for A20+
deletion in adoptive CD8 T-cell therapy, OncoImmunology, 3:10, e958951, DOI: 10.4161/21624011.2014.958951 To link to this article: http://dx.doi.org/10.4161/21624011.2014.958951
Accepted author version posted online: 29 Oct 2014.
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Date: 14 November 2015, At: 07:29
AUTHOR'S VIEW OncoImmunology 3:10, e958951; October 1, 2014; © 2014 Taylor & Francis Group, LLC
Unleashing antitumor T-cell activation without ensuing autoimmunity: the case for A20-deletion in adoptive CD8C T-cell therapy Gr egory Verdeil1,2,3,* and Anne-Marie Schmitt-Verhulst1,2,3 1
Centre d’Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Universite; Marseille Cedex, France; 2INSERM U1104; Marseille, France; 3CNRS UMR7280; Marseille, France
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Keywords: A20/Tnfaip3, adoptive T cell therapy, autoimmunity, melanoma, PD-1
Mechanisms controlling immune reactivity prevent excessive inflammation and autoimmunity, but generally dampen antitumor activity. We recently showed that adoptively transferred antitumor CD8C T cells harboring a deletion of A20/Tnfaip3, a molecule controlling NF-kB activation, possessed heightened antitumor activity in vivo. The boosted immunity of A20-deleted CD8C T cells correlated with a heightened capacity to produce IFNg and TNFa while expressing reduced levels of the immune checkpoint molecule PD-1.
Tumor development is associated with various immunosuppressive mechanisms that affect T-cell responses, including those potentially elicited by antitumor vaccination or adoptive immunotherapy. To increase the efficiency of such therapies one can try either to decrease the immunosuppressive environment created by the tumor or to render T cells less susceptible to immunosuppression. The latter strategies include blockade of inhibitory receptors with monoclonal Ab1 or manipulation of expression of genes that positively2 or negatively3,4 regulate T-cell activation. T cells infiltrating neoplasms are frequently dysfunctional and express surface molecules characteristic of chronically virus-stimulated T cells, often termed “exhausted” T cells. In the TiRP mouse model of induced melanoma, tumorintrinsic factors control the development of aggressive tumors and their expression of an inflammatory/immunosuppressive program.5,6 Intratumoral T cells express inhibitory receptors such as programmed cell death 1 (PDCD1, better known as PD-1) and display low levels of granzyme B as well as a poor capacity to produce either interferon g (IFNg) or tumor necrosis factor a (TNFa) upon restimulation, suggesting that they are exhausted.2,5 In this model we showed that CD8C
tumor-infiltrating lymphocytes (TILs) express elevated levels of tumor necrosis factor induced protein 3 (Tnfaip3, better known as A20) transcripts compared to either na€ıve or acutely activated CD8C T cells. A20, an ubiquitin-modifying enzyme, is one of the major inhibitors of the canonical NF-kB signaling pathway through a mechanism that has not been fully elucidated.7 Causal mutations that control either the level of expression or the function of A20 have been characterized in patients affected with systemic lupus erythematosus or psoriasis, and mice with selective deletion of A20 in B, myeloid or dendritic cells present various forms of autoimmune pathologies (reviewed in ref.7). We recently tested the role of A20 in regulation of CD8C T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells.3 These mice developed lymphadenopathy and some organ-infiltration by T cells. This infiltration was dependent on the presence of both CD4C and CD8C A20-deleted conventional T cells. There was no detectable splenomegaly nor pathology in the mice. A20-deleted CD8C T cells had increased sensitivity to antigen stimulation with production of large amounts of interleukin 2 (IL-2) and IFNg, correlated with the sustained
nuclear presence of NF-kB components cRel/RelA. Over-expression of A20 in this same immune compartment by retroviral transduction of tumor antigen-specific CD8C T cells dampened their intratumoral accumulation and antitumor activity. In contrast, relief from the A20-brake in NF-kB activation in adoptively transferred antitumor CD8C T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8C T cells displayed enhanced production of IFNg and TNFa (Fig. 1A and B). Previously described intratumoral effects of IFNg, either alone or in synergy with TNFa, include the activation of tumorassociated macrophages toward a tumoricidal program, angiostatic effects, and the destruction of tumor stroma.8 However, in contrast to its beneficial antitumor effects, IFNg has also been found to contribute to the adaptive immune resistance of tumor cells by virtue of its ability to upregulate the expression of tumor cell surface PD-L1, one of the ligands of the inhibitory receptor PD-1.1 Therefore, it was important to observe that tumor-infiltrating A20-deleted CD8C T cells showed reduced expression of the inhibitory receptor PD-1 in comparison with tumorinfiltrating control adoptively transferred (Fig. 1A and B) or tumor-endogenous3 CD8C T cells. Although the mechanism
*Correspondence to: Gregory Verdeil; Email:[email protected] Submitted: 08/19/2014; Accepted: 08/23/2014 http://dx.doi.org/10.4161/21624011.2014.958951
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OncoImmunology
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expression on tumor cells and objective response to the treatment.9 We further observed that presence of A20-deleted CD8C T cells led to the bystander activation of tumor-endogenous natural killer (NK) cells that showed an increased expression of the cytolysis-associated enzyme granzyme B. Whether this effect results from the increase in intratumoral production of IFNg and TNFa and/ or additional cytokines (e.g., IL-2) remains to be established. Importantly, bystander activation of NK cells may additionally contribute to contain tumor cell escape from T-cell therapy resulting from tumor antigen or MHC-loss variants.10 Our study demonstrated that A20 represents a major brake on NF-kB activation and cytokine production by intratumoral T cells, yet manipulation of A20 expression in T cells did not result in detectable pathology in the mice. Figure 1. A20 deletion in adoptively transferred CD8C T cells unleashes antitumor activity without eliciting This work thus contributed to autoimmunity. A20-deletion in adoptively transferred antitumor CD8C T cells led to heightened antitumor the identification of a major pathactivity in vivo correlated with their high capacity to produce interferon g (IFNg) and tumor necrosis factor way affected in dysfunctional T a (TNFa), their expression of reduced levels of programmed cell death 1 (PD-1), and a bystander activation cells within tumors, which can of tumor-endogenous natural killer (NK) cells. Tumor antigen-specific CD8C T cells from wild type (WT) mice (A) or from mice with conditional A20-deletion in more than 80% of CD8C T cells (B) were pre-actiapparently be reversed without vated in vitro and adoptively transferred in mice that were inoculated with a melanoma line 7 d earlier. 7 pathologic consequences. This d after adoptive T cell injection the transferred A20-deleted CD8C tumor-infiltrating lymphocytes (TILs) contrasts with approaches of antiwere found to produce high levels of IFNg and TNFa when stimulated ex vivo and to have a moderate C body-mediated blockade of negaexpression level of PD-1 (B) as compared to the transferred WT CD8 TILS (A). Endogenous NK cells tive receptors on T cells such as expressed higher levels of granzyme B (GzmB) when present within the melanomas of mice transferred with A20-deleted (B) as compared to those of mice transferred with WT (A) antitumor CD8C T cells. Of CTLA-4 and PD-1, which showed note the characteristics of CD8C T cells present in autochthonous melanomas induced in the TiRP mice clinical benefit for treatment of was similar to that depicted in A. various solid tumors in some patients, but generally at the cost that leads to the reduced expression of L1.1 Consistent with the notion of the of autoimmune toxicities.1,9 PD-1 was not elucidated, it may contrib- contribution of PD-1/PD-L1 to tumor ute to the enhanced efficiency of A20- immune resistance, treatment of melaDisclosure of Potential Conflicts of Interest deleted antitumor CD8C T cells, particu- noma patients with anti-PD-1 antibody larly in view of the T-cell inhibitory effects has proven efficacious for some patients No potential conflicts of interest were of engagement of PD-1 by its ligand PD- with a correlation between PD-L1 disclosed. References 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252-64; PMID:22437870; http://dx.doi.org/10.1038/nrc3239 2. Auphan-Anezin N, Verdeil G, Grange M, Soudja SM, Wehbe M, Buferne M, Mas A, Schmitt-Verhulst AM. Immunosuppression in inflammatory melanoma: can it be resisted by adoptively transferred T cells? Pigment Cell Melanoma Res 2013; 26:167-75; PMID:23217139; http://dx.doi.org/10.1111/pcmr.12056 3. Giordano M, Roncagalli R, Bourdely P, Chasson L, Buferne M, Yamasaki S, Beyaert R, van Loo G,
e958951-2
Auphan-Anezin N, Schmitt-Verhulst AM, et al. The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells. Proc Natl Acad Sci U S A 2014; 111:11115-20; PMID:25024217; http://dx.doi.org/ 10.1073/pnas.1406259111 4. Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan SK, Cowley GS, Elpek K, et al. In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 2014; 506:52-7; PMID:24476824; http://dx.doi.org/ 10.1038/nature12988
OncoImmunology
5. Soudja SM, Wehbe M, Mas A, Chasson L, de Tenbossche CP, Huijbers I, Van den Eynde B, Schmitt-Verhulst AM. Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice. Cancer Res 2010; 70:3515-25; PMID:20406967; http://dx.doi.org/10.1158/00085472.CAN-09-4354 6. Wehbe M, Soudja SM, Mas A, Chasson L, Guinamard R, de Tenbossche CP, Verdeil G, Van den Eynde B, Schmitt-Verhulst AM. Epithelial-mesenchymal-transition-like and TGFbeta pathways associated with autochthonous inflammatory melanoma development
Volume 3 Issue 10
antigen-loss variants in established mouse cancers. J Clin Invest 2008; 118:1398-404; PMID:18317595; http://dx.doi.org/10.1172/JCI33522 9. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Eng J Med
2012; 366:2443-54; PMID:22658127; http://dx.doi.org/ 10.1056/NEJMoa1200690 10. Shanker A, Verdeil G, Buferne M, Inderberg-Suso EM, Puthier D, Joly F, Nguyen C, Leserman L, AuphanAnezin N, Schmitt-Verhulst AM. CD8 T cell help for innate antitumor immunity. J Immunol 2007; 179:6651-62; PMID:17982055; http://dx.doi.org/ 10.4049/jimmunol.179.10.6651
Downloaded by [Washington University in St Louis] at 07:29 14 November 2015
in mice. PLoS One 2012; 7:e49419; PMID:23173060; http://dx.doi.org/10.1371/journal.pone.0049419 7. Catrysse L, Vereecke L, Beyaert R, van Loo G. A20 in inflammation and autoimmunity. Trends Immunol 2014; 35:22-31; PMID:24246475; http://dx.doi.org/ 10.1016/j.it.2013.10.005 8. Zhang B, Karrison T, Rowley DA, Schreiber H. IFNgamma- and TNF-dependent bystander eradication of
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OncoImmunology
e958951-3
ISSN: (Print) 2162-402X (Online) Journal homepage: http://www.tandfonline.com/loi/koni20
Unleashing antitumor T-cell activation without ensuing autoimmunity: the case for A20-deletion + in adoptive CD8 T-cell therapy Grégory Verdeil & Anne-Marie Schmitt-Verhulst To cite this article: Grégory Verdeil & Anne-Marie Schmitt-Verhulst (2014) Unleashing antitumor T-cell activation without ensuing autoimmunity: the case for A20+
deletion in adoptive CD8 T-cell therapy, OncoImmunology, 3:10, e958951, DOI: 10.4161/21624011.2014.958951 To link to this article: http://dx.doi.org/10.4161/21624011.2014.958951
Accepted author version posted online: 29 Oct 2014.
Submit your article to this journal
Article views: 47
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=koni20 Download by: [Washington University in St Louis]
Date: 14 November 2015, At: 07:29
AUTHOR'S VIEW OncoImmunology 3:10, e958951; October 1, 2014; © 2014 Taylor & Francis Group, LLC
Unleashing antitumor T-cell activation without ensuing autoimmunity: the case for A20-deletion in adoptive CD8C T-cell therapy Gr egory Verdeil1,2,3,* and Anne-Marie Schmitt-Verhulst1,2,3 1
Centre d’Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Universite; Marseille Cedex, France; 2INSERM U1104; Marseille, France; 3CNRS UMR7280; Marseille, France
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Keywords: A20/Tnfaip3, adoptive T cell therapy, autoimmunity, melanoma, PD-1
Mechanisms controlling immune reactivity prevent excessive inflammation and autoimmunity, but generally dampen antitumor activity. We recently showed that adoptively transferred antitumor CD8C T cells harboring a deletion of A20/Tnfaip3, a molecule controlling NF-kB activation, possessed heightened antitumor activity in vivo. The boosted immunity of A20-deleted CD8C T cells correlated with a heightened capacity to produce IFNg and TNFa while expressing reduced levels of the immune checkpoint molecule PD-1.
Tumor development is associated with various immunosuppressive mechanisms that affect T-cell responses, including those potentially elicited by antitumor vaccination or adoptive immunotherapy. To increase the efficiency of such therapies one can try either to decrease the immunosuppressive environment created by the tumor or to render T cells less susceptible to immunosuppression. The latter strategies include blockade of inhibitory receptors with monoclonal Ab1 or manipulation of expression of genes that positively2 or negatively3,4 regulate T-cell activation. T cells infiltrating neoplasms are frequently dysfunctional and express surface molecules characteristic of chronically virus-stimulated T cells, often termed “exhausted” T cells. In the TiRP mouse model of induced melanoma, tumorintrinsic factors control the development of aggressive tumors and their expression of an inflammatory/immunosuppressive program.5,6 Intratumoral T cells express inhibitory receptors such as programmed cell death 1 (PDCD1, better known as PD-1) and display low levels of granzyme B as well as a poor capacity to produce either interferon g (IFNg) or tumor necrosis factor a (TNFa) upon restimulation, suggesting that they are exhausted.2,5 In this model we showed that CD8C
tumor-infiltrating lymphocytes (TILs) express elevated levels of tumor necrosis factor induced protein 3 (Tnfaip3, better known as A20) transcripts compared to either na€ıve or acutely activated CD8C T cells. A20, an ubiquitin-modifying enzyme, is one of the major inhibitors of the canonical NF-kB signaling pathway through a mechanism that has not been fully elucidated.7 Causal mutations that control either the level of expression or the function of A20 have been characterized in patients affected with systemic lupus erythematosus or psoriasis, and mice with selective deletion of A20 in B, myeloid or dendritic cells present various forms of autoimmune pathologies (reviewed in ref.7). We recently tested the role of A20 in regulation of CD8C T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells.3 These mice developed lymphadenopathy and some organ-infiltration by T cells. This infiltration was dependent on the presence of both CD4C and CD8C A20-deleted conventional T cells. There was no detectable splenomegaly nor pathology in the mice. A20-deleted CD8C T cells had increased sensitivity to antigen stimulation with production of large amounts of interleukin 2 (IL-2) and IFNg, correlated with the sustained
nuclear presence of NF-kB components cRel/RelA. Over-expression of A20 in this same immune compartment by retroviral transduction of tumor antigen-specific CD8C T cells dampened their intratumoral accumulation and antitumor activity. In contrast, relief from the A20-brake in NF-kB activation in adoptively transferred antitumor CD8C T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8C T cells displayed enhanced production of IFNg and TNFa (Fig. 1A and B). Previously described intratumoral effects of IFNg, either alone or in synergy with TNFa, include the activation of tumorassociated macrophages toward a tumoricidal program, angiostatic effects, and the destruction of tumor stroma.8 However, in contrast to its beneficial antitumor effects, IFNg has also been found to contribute to the adaptive immune resistance of tumor cells by virtue of its ability to upregulate the expression of tumor cell surface PD-L1, one of the ligands of the inhibitory receptor PD-1.1 Therefore, it was important to observe that tumor-infiltrating A20-deleted CD8C T cells showed reduced expression of the inhibitory receptor PD-1 in comparison with tumorinfiltrating control adoptively transferred (Fig. 1A and B) or tumor-endogenous3 CD8C T cells. Although the mechanism
*Correspondence to: Gregory Verdeil; Email:[email protected] Submitted: 08/19/2014; Accepted: 08/23/2014 http://dx.doi.org/10.4161/21624011.2014.958951
www.landesbioscience.com
OncoImmunology
e958951-1
Downloaded by [Washington University in St Louis] at 07:29 14 November 2015
expression on tumor cells and objective response to the treatment.9 We further observed that presence of A20-deleted CD8C T cells led to the bystander activation of tumor-endogenous natural killer (NK) cells that showed an increased expression of the cytolysis-associated enzyme granzyme B. Whether this effect results from the increase in intratumoral production of IFNg and TNFa and/ or additional cytokines (e.g., IL-2) remains to be established. Importantly, bystander activation of NK cells may additionally contribute to contain tumor cell escape from T-cell therapy resulting from tumor antigen or MHC-loss variants.10 Our study demonstrated that A20 represents a major brake on NF-kB activation and cytokine production by intratumoral T cells, yet manipulation of A20 expression in T cells did not result in detectable pathology in the mice. Figure 1. A20 deletion in adoptively transferred CD8C T cells unleashes antitumor activity without eliciting This work thus contributed to autoimmunity. A20-deletion in adoptively transferred antitumor CD8C T cells led to heightened antitumor the identification of a major pathactivity in vivo correlated with their high capacity to produce interferon g (IFNg) and tumor necrosis factor way affected in dysfunctional T a (TNFa), their expression of reduced levels of programmed cell death 1 (PD-1), and a bystander activation cells within tumors, which can of tumor-endogenous natural killer (NK) cells. Tumor antigen-specific CD8C T cells from wild type (WT) mice (A) or from mice with conditional A20-deletion in more than 80% of CD8C T cells (B) were pre-actiapparently be reversed without vated in vitro and adoptively transferred in mice that were inoculated with a melanoma line 7 d earlier. 7 pathologic consequences. This d after adoptive T cell injection the transferred A20-deleted CD8C tumor-infiltrating lymphocytes (TILs) contrasts with approaches of antiwere found to produce high levels of IFNg and TNFa when stimulated ex vivo and to have a moderate C body-mediated blockade of negaexpression level of PD-1 (B) as compared to the transferred WT CD8 TILS (A). Endogenous NK cells tive receptors on T cells such as expressed higher levels of granzyme B (GzmB) when present within the melanomas of mice transferred with A20-deleted (B) as compared to those of mice transferred with WT (A) antitumor CD8C T cells. Of CTLA-4 and PD-1, which showed note the characteristics of CD8C T cells present in autochthonous melanomas induced in the TiRP mice clinical benefit for treatment of was similar to that depicted in A. various solid tumors in some patients, but generally at the cost that leads to the reduced expression of L1.1 Consistent with the notion of the of autoimmune toxicities.1,9 PD-1 was not elucidated, it may contrib- contribution of PD-1/PD-L1 to tumor ute to the enhanced efficiency of A20- immune resistance, treatment of melaDisclosure of Potential Conflicts of Interest deleted antitumor CD8C T cells, particu- noma patients with anti-PD-1 antibody larly in view of the T-cell inhibitory effects has proven efficacious for some patients No potential conflicts of interest were of engagement of PD-1 by its ligand PD- with a correlation between PD-L1 disclosed. References 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252-64; PMID:22437870; http://dx.doi.org/10.1038/nrc3239 2. Auphan-Anezin N, Verdeil G, Grange M, Soudja SM, Wehbe M, Buferne M, Mas A, Schmitt-Verhulst AM. Immunosuppression in inflammatory melanoma: can it be resisted by adoptively transferred T cells? Pigment Cell Melanoma Res 2013; 26:167-75; PMID:23217139; http://dx.doi.org/10.1111/pcmr.12056 3. Giordano M, Roncagalli R, Bourdely P, Chasson L, Buferne M, Yamasaki S, Beyaert R, van Loo G,
e958951-2
Auphan-Anezin N, Schmitt-Verhulst AM, et al. The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells. Proc Natl Acad Sci U S A 2014; 111:11115-20; PMID:25024217; http://dx.doi.org/ 10.1073/pnas.1406259111 4. Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan SK, Cowley GS, Elpek K, et al. In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 2014; 506:52-7; PMID:24476824; http://dx.doi.org/ 10.1038/nature12988
OncoImmunology
5. Soudja SM, Wehbe M, Mas A, Chasson L, de Tenbossche CP, Huijbers I, Van den Eynde B, Schmitt-Verhulst AM. Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice. Cancer Res 2010; 70:3515-25; PMID:20406967; http://dx.doi.org/10.1158/00085472.CAN-09-4354 6. Wehbe M, Soudja SM, Mas A, Chasson L, Guinamard R, de Tenbossche CP, Verdeil G, Van den Eynde B, Schmitt-Verhulst AM. Epithelial-mesenchymal-transition-like and TGFbeta pathways associated with autochthonous inflammatory melanoma development
Volume 3 Issue 10
antigen-loss variants in established mouse cancers. J Clin Invest 2008; 118:1398-404; PMID:18317595; http://dx.doi.org/10.1172/JCI33522 9. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Eng J Med
2012; 366:2443-54; PMID:22658127; http://dx.doi.org/ 10.1056/NEJMoa1200690 10. Shanker A, Verdeil G, Buferne M, Inderberg-Suso EM, Puthier D, Joly F, Nguyen C, Leserman L, AuphanAnezin N, Schmitt-Verhulst AM. CD8 T cell help for innate antitumor immunity. J Immunol 2007; 179:6651-62; PMID:17982055; http://dx.doi.org/ 10.4049/jimmunol.179.10.6651
Downloaded by [Washington University in St Louis] at 07:29 14 November 2015
in mice. PLoS One 2012; 7:e49419; PMID:23173060; http://dx.doi.org/10.1371/journal.pone.0049419 7. Catrysse L, Vereecke L, Beyaert R, van Loo G. A20 in inflammation and autoimmunity. Trends Immunol 2014; 35:22-31; PMID:24246475; http://dx.doi.org/ 10.1016/j.it.2013.10.005 8. Zhang B, Karrison T, Rowley DA, Schreiber H. IFNgamma- and TNF-dependent bystander eradication of
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OncoImmunology
e958951-3
