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Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice

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Abstract

Cytotoxic T lymphocyte (CTL) can have remarkable abilities to kill tumor cells. However, the establishment of successful CTL-based anticancer therapy has met with many challenges. Within tumor cells, there exist subpopulations with low or no expression of the targeted antigen (termed as antigen-loss variants). In addition, tumor cells can downregulate the levels of major histocompatibility complex class I (MHC-I) molecules on cell surface due to immune pressure. As a result, some tumor cells can escape the immune pressure bestowed by CTLs, resulting in treatment failure. To address these difficulties, a new approach is developed to deliver foreign high-affinity CTL epitopes to tumor tissues utilizing pH-responsive “smart” microparticles (MPs). These MPs could encapsulate CTL peptide epitope, release the peptide under acidic condition encountered in tumor tissues and enhance CTL activation. Mice bearing pre-established tumor as “antigen-loss variant” solid tumor models were administered intratumorally with MPs containing the CTL peptide, which showed 100% survival following the treatment. In contrast, all control mice died from tumor. Significant protection from tumor-induced death was also observed with systemic administration of CTL peptide-MPs. The therapeutic efficacy can be attributed to enhanced delivery of the epitope to tumor tissues, presentation of the epitope by tumor cells as well as tumor stromal cells and/or generation of epitope-specific CTLs by the peptide-containing MPs. These findings offer a promising new direction for treating established solid tumor using CTL therapy.

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Abbreviations

7-AAD:

7-Aminoactinomycin D

ACE-Dex:

Acetalated dextran

ALV:

Antigen-loss variant

CFSE:

Carboxyfluorescein succinimidyl ester

CRPG:

Chlorophenol red-β-d-galactopyranoside

CTL:

Cytotoxic T lymphocyte

CTLp:

CTL peptide epitope

DCM:

Dichloromethane

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

FACS:

Fluorescence-activated cell sorting

FBS:

Fetal bovine serum

Fmoc:

Fluorenylmethyloxycarbonyl

HBSS:

Hank’s balanced salt solution

mAb:

Monoclonal antibody

MHC-I:

Major histocompatibility complex class I

MP:

Microparticle

PBS:

Phosphate-buffered saline

PE:

Phycoerythrin

RPMI:

Roswell Park Memorial Institute

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Acknowledgements

We are grateful to the National Cancer Institute (R01CA149451) for financial support of this work. We would like to thank Prof. Olivera J. Finn (University of Pittsburgh) for helpful suggestions.

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    Authors and Affiliations

    1. Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA

      Herbert W. Kavunja, Shuyao Lang, Suttipun Sungsuwan, Zhaojun Yin & Xuefei Huang

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    Correspondence to Xuefei Huang.

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    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal care procedures and experimental protocols performed were in accordance with the ethical standards and have been approved by the Institutional Animal Care and Use Committee (IACUC) of Michigan State University.

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    Herbert W. Kavunja and Shuyao Lang have contributed equally to this work.

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    Kavunja, H.W., Lang, S., Sungsuwan, S. et al. Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice. Cancer Immunol Immunother 66, 451–460 (2017). https://doi.org/10.1007/s00262-016-1948-9

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    • DOI: https://doi.org/10.1007/s00262-016-1948-9

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