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Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors

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Abstract

Adoptive T cell transfer (ACT) has achieved clinical success in treating established cancer, particularly in combination with lymphodepleting regimens. Our group previously demonstrated that ACT following whole-body irradiation (WBI) promotes high-level T cell accumulation, regression of established brain tumors, and long-term protection from tumor recurrence in a mouse model of SV40 T antigen-induced choroid plexus tumors. Here we asked whether an approach that can promote strong donor T-cell responses in the absence of WBI might also produce this dramatic and durable tumor elimination following ACT. Agonist anti-CD40 antibody can enhance antigen-specific CD8+ T-cell responses and has shown clinical efficacy as a monotherapy in the setting of cancer. We show that anti-CD40 conditioning promotes rapid accumulation of tumor-specific donor CD8+ T cells in the brain and regression of autochthonous T antigen-induced choroid plexus tumors, similar to WBI. Despite a significant increase in the lifespan, tumors eventually recurred in anti-CD40-conditioned mice coincident with loss of T-cell persistence from both the brain and lymphoid organs. Depletion of CD8+ T cells from the peripheral lymphoid organs of WBI-conditioned recipients failed to promote tumor recurrence, but donor cells persisted in the brains long-term in CD8-depleted mice. These results demonstrate that anti-CD40 conditioning effectively enhances ACT-mediated acute elimination of autochthonous tumors, but suggest that mechanisms associated with WBI conditioning, such as the induction of long-lived T cells, may be critical for protection from tumor recurrence.

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Abbreviations

ACT:

Adoptive T-cell transfer

cLN:

Superficial cervical lymph nodes

FITC:

Fluorescein isothiocyanate

H&E:

Hematoxylin and eosin

IFN:

Interferon

IL:

Interleukin

i.p.:

Intraperitoneal

KLRG1:

Killer cell lectin-like receptor G1

NBF:

Neutral buffered formalin

pAPC:

Professional antigen-presenting cell

RBC:

Red blood cell

SV40:

Simian virus 40

T Ag:

SV40 large T antigen

TCR:

T-cell receptor

WBI:

Whole-body irradiation

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Acknowledgments

We thank Jeremy Haley for outstanding technical assistance and Penn State Hershey Flow Cytometry Core Facility personnel for support with data acquisition. This work was supported by research Grant RO1 CA025000 from the National Cancer Institute, National Institutes of Health (to Todd Schell). Portions of this work were previously published and presented in an abstract and poster at the Translational Research Cancer Centers Consortium in Seven Springs, PA in February of 2014.

Conflict of interest

All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Penn State Hershey College of Medicine, 500 University Drive, H107, Hershey, PA, 17033, USA

    Eugene M. Cozza, Neil D. Christensen & Todd D. Schell

  2. Department of Comparative Medicine, Penn State Hershey College of Medicine, Hershey, PA, 17033, USA

    Timothy K. Cooper

  3. Department of Pathology, Penn State Hershey College of Medicine, Hershey, PA, 17033, USA

    Timothy K. Cooper, Lynn R. Budgeon & Neil D. Christensen

  4. Penn State Hershey Cancer Institute, Hershey, PA, 17033, USA

    Neil D. Christensen & Todd D. Schell

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  1. Eugene M. Cozza
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  2. Timothy K. Cooper
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  3. Lynn R. Budgeon
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  5. Todd D. Schell
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Correspondence to Todd D. Schell.

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Cozza, E.M., Cooper, T.K., Budgeon, L.R. et al. Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors. Cancer Immunol Immunother 64, 325–336 (2015). https://doi.org/10.1007/s00262-014-1635-7

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