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Anti-tumor activity and trafficking of self, tumor-specific T cells against tumors located in the brain

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Abstract

It is commonly believed that T cells have difficulty reaching tumors located in the brain due to the presumed “immune privilege” of the central nervous system (CNS). Therefore, we studied the biodistribution and anti-tumor activity of adoptively transferred T cells specific for an endogenous tumor-associated antigen (TAA), gp100, expressed by tumors implanted in the brain. Mice with pre-established intracranial (i.c.) tumors underwent total body irradiation (TBI) to induce transient lymphopenia, followed by the adoptive transfer of gp10025–33-specific CD8+ T cells (Pmel-1). Pmel-1 cells were transduced to express the bioluminescent imaging (BLI) gene luciferase. Following adoptive transfer, recipient mice were vaccinated with hgp10025–33 peptide-pulsed dendritic cells (hgp10025–33/DC) and systemic interleukin 2 (IL-2). This treatment regimen resulted in significant reduction in tumor size and extended survival. Imaging of T cell trafficking demonstrated early accumulation of transduced T cells in lymph nodes draining the hgp10025–33/DC vaccination sites, the spleen and the cervical lymph nodes draining the CNS tumor. Subsequently, transduced T cells accumulated in the bone marrow and brain tumor. BLI could also detect significant differences in the expansion of gp100-specific CD8+ T cells in the treatment group compared with mice that did not receive either DC vaccination or IL-2. These differences in BLI correlated with the differences seen both in survival and tumor infiltrating lymphocytes (TIL). These studies demonstrate that peripheral tolerance to endogenous TAA can be overcome to treat tumors in the brain and suggest a novel trafficking paradigm for the homing of tumor-specific T cells that target CNS tumors.

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Abbreviations

BLI:

Bioluminescent imaging

CNS:

Central nervous system

DC:

Dendritic cell

TAA:

Tumor-associated antigen

i.c.:

Intracranial

TBI:

Total body irradiation

TIL:

Tumor-infiltrating lymphocytes

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Acknowledgments

This work was supported in part by NIH/NCI grants K01 CA111402 (to RMP), R01 CA 112358 (to LML), P50 CA086306 (to AR), the Philip R. and Kenneth A. Jonsson Foundations (to LML), the Musella Foundation for Brain Tumor Research (to LML and RMP), and the Neidorf Family Foundation (to LML and RMP). ONW is an investigator of the Howard Hughes Medical Institute. CGR was supported by the In Vivo Cellular and Molecular Imaging Centers (ICMIC) Developmental Project Award. CJS was supported by the Pharmacological Sciences Training grant PHS T32 CM008652. RMP is the recipient of the Howard Temin NCI Career Development award. AR is the recipient of a STOP Cancer Career Development award and K23 CA93376.

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Authors and Affiliations

  1. Department of Surgery, Division of Neurosurgery, David Geffen School of Medicine at UCLA, CHS 74-145, 10833 Le Conte Avenue, PO Box 956901, Los Angeles, CA, 90095, USA

    Robert M. Prins, Haumith Khan-Farooqi, Horacio Soto, Meng-Yin Yang, Muh-Shi Lin & Linda M. Liau

  2. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Robert M. Prins & Owen N. Witte

  3. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Robert M. Prins, Caius G. Radu, Owen N. Witte, Antoni Ribas & Linda M. Liau

  4. Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Robert M. Prins & Linda M. Liau

  5. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Chengyi J. Shu, Caius G. Radu, Stephanie Shelly & Owen N. Witte

  6. Department of Surgery, Division of Surgical Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Dan D. Vo & Antoni Ribas

  7. Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Owen N. Witte

  8. Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Antoni Ribas

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  1. Robert M. Prins
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  2. Chengyi J. Shu
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Correspondence to Robert M. Prins.

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Prins, R.M., Shu, C.J., Radu, C.G. et al. Anti-tumor activity and trafficking of self, tumor-specific T cells against tumors located in the brain. Cancer Immunol Immunother 57, 1279–1289 (2008). https://doi.org/10.1007/s00262-008-0461-1

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