Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs

Zhang, Yue; Wakita, Daiko; Chamoto, Kenji; Narita, Yoshinori; Matsubara, Naoki; Kitamura, Hiroyuki; Nishimura, Takashi

doi:10.1093/intimm/dxl132

Cited by 28 publications

(32 citation statements)

References 44 publications

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“…These findings indicate that the model cancer vaccine is shifting the balance from a tolerogenic to an immunogenic microenvironment in the tumor. Similarly, other studies have found that Tregs infiltrated the tdLN less when targeted with a cellular therapy in tumor-bearing mice (44).…”

Section: Discussionmentioning

confidence: 65%

“…4B) induced by targeting the vaccine to the tdLN led to regression of early-stage tumors and more impressively of tumors having reached the Swiss legal limit of 1 cm 3 . In the literature, cancer vaccines are usually administered when the tumors are 5 to 7 mm in diameter or even before they are detectable, and also do not usually induce this high number of TAA-specific CD8 þ T cells in the blood and the LNs (17,19,30,38,44), thus emphasizing the benefits of nanoparticle-mediated targeting of antigen and adjuvant to DCs in the tdLN (18,38,45). We noted, however, that after regressing some tumors grew back.…”

Section: Discussionmentioning

confidence: 80%

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Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

175

133

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The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in nontumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8 þ T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. Cancer Immunol Res; 2(5); 436-47. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 80%

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

175

133

View full text Add to dashboard Cite

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“…Thus, our results indicate that IL-17-producing gd T cells act as pro-but not anti-tumor effector cells in tumorgrowing microenvironment. In our previous work [16][17][18][19][20], we have proposed that the introduction of Th1-dominant immunity overcomes strong immunosuppression in tumor-bearing host and induces complete cure of the tumor-bearing mice. Therefore, we now investigated whether Th1 cell therapy or introduction of Th1 immunity by IL-12 can induce a plasticity in IL-17-producing gd T cells, namely, alter pro-to anti-tumor IL-17-producing gd T cells.…”

Section: Discussionmentioning

confidence: 99%

“…We have proposed that the induction of Th1-dominant immune responses is an essential step in inducing strong anti-tumor immunity in response to adjuvants or tumor-specific Th1 cells [16][17][18][19][20]. However, within the tumor microenvironment, the balance between IL-12 and IL-23, which directly reflects Th1 and Th17 cell responses, is shifted toward IL-23 via activation of STAT3 [21,22].…”

Section: Introductionmentioning

confidence: 99%

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

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Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing cd T cells for tumor development in tumor-bearing mouse model. IL-17 À/À mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), cd T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-cd T cells showed that circulating cd T cells, but not skin resident Vc5 1 cd T cells, produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-b, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing cd T cells. IL-17 production by tumor-infiltrating cd T cells was blocked by anti-cdTCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in cd T-cell activation. The IL-17-producing TIL-cd T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing cd T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis. IntroductionIn order to understand how tumor cells can escape immune surveillance mechanisms and thus develop anti-tumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. The tumor microenvironment, which is mainly composed of tumor cells, stromal cells, and tumor-infiltrating immune cells, is entirely different from noncancerous tissues. This unique microenvironment potently inhibits immune responses against tumor cells via various soluble mediators and contact-dependent mechanisms [1,2]. Previously, it was suggested that T-cell Eur. J. Immunol. 2010. 40: 1927-1937 DOI 10.1002 Cellular immune response 1927 responses within the local tumor tissue are completely inhibited. However, this concept was abandoned following the discovery of the regulatory T-cell and Th17 cell subsets, which are activated rather than suppressed in the tumor microenvironment via TGF-b and/or IL-6. Thus, the tumor microenvironment is conducive to IL-17 production. In fact, it has been shown that IL-17 is produced in human and murine tumor tissues [3][4][5]. Tumor cells promote neo-vascularization into tumor tissues through hyperproduction of angiogenic factors, which also support their own abnormal proliferation and survival [6]. It has been reported that tumor cells over-expressing IL-17 significantly promote new vessel growth into the tumor tissues [5]; however, physiological effects of IL-17 on tumor progression remain to be defined. Th17 differentiation from naïve CD4 1 T cells is regulated by TGF-b and IL-6. Proliferation, maintenance and full maturation of these cells are controlled by . Recently, it has been shown that IL-17 is produced by diverse T...

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“…Previously, we have proposed that tumour-specific CD4 þ T cells, especially T-helper type 1 (Th1) cells play a critical role for inducing cytotoxic T lymphocytes (CTL)-mediated antitumour immunity in tumour-bearing mice Ikeda et al, 2004;Chamoto et al, 2006;Zhang et al, 2006). Although many investigators have centred in the activation and targeting of tumour-specific CD8 þ CTL and CD4 þ T cells are required for the priming and maintenance of CD8 þ T cells (Janssen et al, 2003;Smith et al, 2004;Sun et al, 2004).…”

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confidence: 99%

Identification of novel helper epitopes of MAGE-A4 tumour antigen: useful tool for the propagation of Th1 cells

et al. 2009

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MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumour immunotherapy. It has been well accepted that T-helper type 1 (Th1) cell-dominant immunity is critical for the successful induction of antitumour immunity in a tumour-bearing host. The adoptive Th1 cell therapy has been shown to be an attractive strategy for inducing tumour eradication in mouse systems. However, Th1-cell therapy using human tumour-specific Th1 cells, which were expanded from peripheral blood mononuclear cells (PBMCs) in a clinically useful protocol, has never been performed. Here, we first identified MAGE-A4-derived promiscuous helper epitope, peptide (MAGE-A4 280 -299), bound to both HLA-DPB1*0501 and DRB1*1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 cells in vitro. Culture of CD4 þ T cells with IFN-g-treated PBMCderived adherent cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th cells producing IFN-g , but not IL-4. Moreover, it was shown that ligation of MAGE-A4-reactive Th1 cells with the cognate peptide caused the production of IFN-g and IL-2. Thus, our identified MAGE-A4 helper epitope peptide will become a good tool for the propagation of tumour-specific Th1 cells applicable to adoptive immunotherapy of human cancer.

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Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs

Cited by 28 publications

References 44 publications

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

Identification of novel helper epitopes of MAGE-A4 tumour antigen: useful tool for the propagation of Th1 cells

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