Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics

Crompton, J. G., Sukumar, M., Roychoudhuri, R., Clever, D., Gros, A., Eil, R. L., Tran, E., Hanada, K., Yu, Z., Palmer, D. C., Kerkar, S. P., Michalek, R. D., Upham, T., Leonardi, A., Acquavella, N., Wang, E., Marincola, F. M., Gattinoni, L., Muranski, P., Sundrud, M. S., Klebanoff, C. A., Rosenberg, S. A., Fearon, D. T., Restifo, N. P. (January 2015) Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res, 75 (2). pp. 296-305. ISSN 0008-5472

URL: http://www.ncbi.nlm.nih.gov/pubmed/25432172
DOI: 10.1158/0008-5472.can-14-2277

Abstract

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer.

Item Type: Paper
Uncontrolled Keywords: Animals Humans Immunologic Memory Immunotherapy, Adoptive/*methods Lymphocytes, Tumor-Infiltrating/drug effects/*immunology/pathology Melanoma/immunology/*therapy Melanoma, Experimental/immunology/*therapy Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Transgenic Protein Kinase Inhibitors/*pharmacology Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/immunology Random Allocation Tumor Cells, Cultured
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL labs > Fearon lab
Depositing User: Matt Covey
Date: 15 January 2015
Date Deposited: 15 Oct 2015 20:31
Last Modified: 15 Oct 2015 20:31
PMCID: PMC4384335
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31927

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