The Brain Parenchyma Is Permissive for Full Antitumor CTL Effector Function, Even in the Absence of CD4 T Cells

Walker, Paul R; Calzascia, Thomas; Schnüriger, Valérie; Scamuffa, Nathalie; Saas, Philippe; Tribolet, Nicolas de; Dietrich, Pierre‐Yves

doi:10.4049/jimmunol.165.6.3128

Cited by 47 publications

(49 citation statements)

References 62 publications

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“…Thus, our data provide evidence that modulation of CD8 + T cell function is a potential strategy to improve therapy against a wide range of diseases that occur in the brain. Given the proposed roles for CD8 + T cells in mediating or protecting against numerous brain-related diseases, such as viral encephalitis (58)(59)(60), toxoplasmosis (61,62), multiple sclerosis (63-65), brain tumors (29,31,66), and cerebral listeriosis (67)(68)(69), our data have implications that extend beyond ECM to other infectious diseases, cancer, and autoimmunity.…”

Section: Discussionmentioning

confidence: 92%

“…The brain is uniquely isolated from its own vasculature by the blood-brain barrier (BBB) (26), and yet CD8 + T cells in the bloodstream can cross into brain parenchymal tissue during infection (27,28), cancer (29)(30)(31), and autoimmune disease (32,33). Recent studies report that local antigenic stimulation may be required either for CD8 + T cell retention and motility arrest in brain microvasculature or crossing the BBB (34)(35)(36).…”

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confidence: 99%

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Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

Haque

Best

Unosson

et al. 2011

The Journal of Immunology

172

210

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Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8+ T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8+ T cells expressed granzyme B (GzmB). Furthermore, gzmB−/− mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4+ T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8+ T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8+ T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8+ T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8+ T cells dictates the onset of perforin/GzmB-mediated ECM.

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

Haque

Best

Unosson

et al. 2011

The Journal of Immunology

172

210

View full text Add to dashboard Cite

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“…Recently, CD8 1 T-cells have also been shown to extravasate to the CNS in mouse brain tumor models. 1,50 However, highly immunogenic foreign antigens were used in these models because no mouse brain tumor antigen had been isolated. The immune responses that occur in the CNS are significantly different from those that occur outside the brain, probably because of the immu- nosuppressive environment, including the low expression of MHC molecules, the absence of dendritic cells and the presence of brain-derived gangliosides that exert inhibitory effects on Tcells.…”

Section: Discussionmentioning

confidence: 99%

Identification of a glioma antigen, GARC‐1, using cytotoxic T lymphocytes induced by HSV cancer vaccine

Iizuka¹,

Kojima²,

Kobata³

et al. 2005

Intl Journal of Cancer

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Despite several ongoing clinical trials of immunotherapies against glioma, few glioma-specific antigens recognized by cytotoxic T lymphocytes (CTLs) have been identified. We recently demonstrated that intratumoral inoculation with herpes simplex virus (HSV) as a cancer vaccine activates tumor-specific CTLs. To identify glioma antigens recognized by CTLs, we used the HSV cancer vaccine to vaccinate mice harboring a syngeneic mouse glioma cell line, GL261. From the splenocytes of the immunized mice, we generated an H-2D b -restricted CTL line, GCL-1, that was specific for GL261. Then, a cDNA expression library generated from GL261 was screened with GCL-1, and a new gene encoding glioma antigen, GARC-1, was isolated. Sequence analysis revealed that the GARC-1 gene isolated from GL261 had a point mutation causing an amino acid change (Asp to Asn at position 81). T-cell epitope analysis revealed that the mutated peptide GARC-1 77-85 (AALLN-KLYA) but not the wild-type peptide (AALLDKLYA), was recognized by GCL-1. These results suggest that HSV cancer vaccination may be a useful method for inducing tumor-specific CTLs and identifying tumor antigens. Furthermore, this GL261/ GARC-1 murine glioma model may be useful for the development of immunotherapy for brain tumors. ' 2005 Wiley-Liss, Inc.Key words: glioma; antigen; CTL; immunotherapy; HSV; G207; GL261; cancer vaccine Malignant brain tumors continue to be a major unsolved health problem throughout the world. Despite aggressive combined treatment modalities, little improvement has been made in the prognosis and survival of patients with malignant gliomas over the last decade. [1][2][3] The standard management of patients with malignant gliomas entails surgical resection followed by radiotherapy and chemotherapy. However, tumor progression inevitably occurs in almost all patients. 4 Therefore, the development of new therapeutic modalities for malignant gliomas is needed.Although the central nervous system (CNS) has long been considered an immunologically privileged site, recent studies have demonstrated that this privileged state is not absolute. [5][6][7][8] The presence of active immunity within the CNS supports the possibility of manipulating the immune system to create effective immunotherapy protocols against gliomas. 9,10 Recent progress in tumor immunology has highlighted the molecules involved in specific tumor immunity, including tumor rejection antigens recognized by CTLs. 11-15 Some of the antigenic peptides encoded by the tumor antigen genes have been used as a peptide-based vaccine in clinical trials for cancer patients, with tumor regression observed in some melanoma patients. 16,17 Despite several ongoing clinical trials of immunotherapies against glioma, however, few glioma antigens recognized by CTLs have been identified. To better understand the immune responses in the CNS and to design immunotherapeutic strategies against gliomas, glioma-specific antigens must be identified.A number of lytic viruses have been used in attempts to induce antitumor imm...

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“…TIL were isolated by enzymatic digestion and modified Ficoll-Hypaque centrifugation as previously described. 27 Briefly, brain tissue was incubated with Collagenase Type IA (50 mg/ml), DNAse Type I (10 lg/ml) and a trypsine inhibitor (Sigma-Aldrich) in Hanks Balanced Salt Solution (HBSS) with Ca 21 , Mg 21 at 37°C. After 45 min EDTA was added (12.5 mM final), a cell suspension was prepared, filtered and transferred to a 15 ml tube.…”

Section: Isolation Of Tumor-infiltrating Lymphocytes and Tumor-derivementioning

confidence: 99%

CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo

Grauer

Nierkens

Bennink

et al. 2007

Intl Journal of Cancer

202

165

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The suppressive activity of regulatory T cells (Treg) has been implicated as an important factor limiting immune mediated destruction of tumor cells. However, not much is known about the presence and function of Treg within tumors. Here we show in a syngeneic murine glioma model a time-dependent accumulation of CD41FoxP31 Treg in brain tumors. Further analysis revealed a time-dependent upregulation of CD25, CTLA-4, GITR and CXCR4 on intratumoral CD41FoxP31 Treg during tumor growth. Moreover, freshly isolated intratumoral Treg were highly suppressive when tested directly ex vivo. Treatment with anti-CD25 monoclonal antibodies (mAbs) significantly reduced the number of these highly suppressive CD41FoxP31 cells within the growing tumor and provoked a CD4 and CD8 T cell dependent destruction of the glioma cells. Combining Treg depletion with administration of blocking CTLA-4 mAbs further boosted gliomaspecific CD41 and CD81 effector T cells as well as antiglioma IgG2a antibody titers resulting in complete tumor eradication without any signs of autoimmunity. These data illustrate that intratumoral accumulation and activation of CD41FoxP31 Treg act as a dominant immune escape mechanism for gliomas and underline the importance of controlling tumor-infiltrating Treg in glioma immunotherapy. ' 2007 Wiley-Liss, Inc. Key words: glioma; regulatory T cell; immune escapeThe naturally occurring CD41 regulatory T cells (Treg) are continuously produced by the thymus and gradually settled in secondary lymphoid organs. They constitute 5-15% of the overall CD41 T cell population and exert a strong suppressive activity on multiple components of the immune system. Although their repertoire in antigen recognition is quite diverse, they preferentially recognize tissue specific self-antigens. As many tumors express self-antigens, CD41 Treg do not only dominantly suppress the activation and expansion of different effector cells capable of mediating autoimmunity, but also effective antitumor responses. 1 So far the most specific marker for naturally occurring CD41 Treg, at least in mice, is FoxP3, a member of the forkhead family of DNA-binding transcription factors. FoxP3 is highly expressed in naturally occurring CD41 Treg and clearly linked to their suppressive function. [2][3][4] Other molecules that are constitutively expressed on CD41 Treg are the IL-2 receptor a-chain (CD25), cytotoxic lymphocyte-associated antigen-4 (CTLA-4) and different members of the tumor necrosis factor (TNF) receptor superfamily like the glucocorticoid-induced TNF related protein (GITR). These molecules, however, do not uniquely distinguish the CD41 Treg from conventional CD41 T cells that can temporally upregulate these molecules following activation. [5][6][7][8][9] Recent data also suggest an important role of Toll-like receptors (TLRs) in controlling Treg. 10 TLR2-triggering on murine Treg in combination with T cell receptor ligation resulted, both in vitro and in vivo, in proliferation of the otherwise anergic Treg. Moreover, the suppressive phenotype o...

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The Brain Parenchyma Is Permissive for Full Antitumor CTL Effector Function, Even in the Absence of CD4 T Cells

Cited by 47 publications

References 62 publications

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

Identification of a glioma antigen, GARC‐1, using cytotoxic T lymphocytes induced by HSV cancer vaccine

CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo

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