Efficacy of synthetic vaccines in the induction of cytotoxic T lymphocytes comparison of the costimulating support provided by helper T cells and lipoamino acid

Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract

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CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

Journal of Experimental Medicine ◽

10.1084/jem.20040717 ◽

2004 ◽

Vol 200 (11) ◽

pp. 1407-1417 ◽

Cited By ~ 92

Author(s):

Adrian F. Ochsenbein ◽

Stanley R. Riddell ◽

Michele Brown ◽

Lawrence Corey ◽

Gabriela M. Baerlocher ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Cd8 T Cells ◽

Interleukin 2 ◽

Tumor Necrosis Factor Receptor ◽

Cell Receptor ◽

Effector Memory ◽

Term Survival ◽

Functional Consequences

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response.

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Regulatory functions of hapten-reactive helper and suppressor T lymphocytes. II. Selective inactivation of hapten-reactive suppressor T cells by hapten-nonimmunogenic copolymers of D-amino acids, and its application to the study of suppressor T-cell effect on helper T-cell development

Journal of Experimental Medicine ◽

10.1084/jem.146.1.91 ◽

1977 ◽

Vol 146 (1) ◽

pp. 91-106 ◽

Cited By ~ 10

Author(s):

T Hamaoka ◽

M Yoshizawa ◽

H Yamamoto ◽

M Kuroki ◽

M Kitagawa

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

T Cell Development ◽

Cell Activity ◽

Helper T Cells ◽

Suppressor T Cells ◽

Helper T Cell ◽

Suppressor T Cell ◽

Suppressor T Lymphocytes

An experimental condition was established in vivo for selectively eliminating hapten-reactive suppressor T-cell activity generated in mice primed with a para-azobenzoate (PAB)-mouse gamma globulin (MGG)-conjugate and treated with PAB-nonimmunogenic copolymer of D-amino acids (D- glutamic acid and D-lysine; D-GL). The elimination of suppressor T-cell activity with PAB-D-GL treatment from the mixed populations of hapten- reactive suppressor and helper T cells substantially increased apparent helper T-cell activity. Moreover, the inhibition of PAB-reactive suppressor T-cell generation by the pretreatment with PAB-D-GL before the PAB-MGG-priming increased the development of PAB-reactive helper T-cell activity. The analysis of hapten-specificity of helper T cells revealed that the reactivity of helper cells developed in the absence of suppressor T cells was more specific for primed PAB-determinants and their cross-reactivities to structurally related determinants such as meta-azobenzoate (MAB) significantly decreased, as compared with the helper T-cell population developed in the presence of suppressor T lymphocytes. In addition, those helper T cells generated in the absence of suppressor T cells were highly susceptible to tolerogenesis by PAB-D- GL. Similarly, the elimination of suppressor T lymphocytes also enhanced helper T-cell activity in a polyclonal fashion in the T-T cell interactions between benzylpenicilloyl (BPO)-reactive T cells and PAB- reactive T cells after immunization of mice with BPO-MGG-PAB. Thus inhibition of BPO-reactive suppressor T-cell development by the BPO-v-GL- pretreatment resulted in augmented generation of PAB-reactive helper T cells with higher susceptibility of tolerogenesis to PAB-D-GL. Thus, these results support the notion that suppressor T cells eventually suppress helper T-cell activity and indicate that the function of suppressor T cells related to helper T-cell development is to inhibit the increase in the specificity and apparent affinity of helper T cells in the primary immune response. The hapten-reactive suppressor and helper T lymphocytes are considered as a model system of T cells that regulate the immune response, and the potential applicability of this system to manipulating various T cell-mediated immune responses is discussed in this context.

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