Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors

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Tahtinen , S , Kaikkonen , S , Merisalo-Soikkeli , M , Gronberg-Vaha-Koskela , S , Kanerva , A , Parviainen , S , Vaha-Koskela , M & Hemminki , A 2015 , ' Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors ' , PLoS One , vol. 10 , no. 6 , 0131242 . https://doi.org/10.1371/journal.pone.0131242

Title: Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors
Author: Tahtinen, Siri; Kaikkonen, Saija; Merisalo-Soikkeli, Maiju; Gronberg-Vaha-Koskela, Susanna; Kanerva, Anna; Parviainen, Suvi; Vaha-Koskela, Markus; Hemminki, Akseli
Contributor: University of Helsinki, Medicum
University of Helsinki, Department of Pathology
University of Helsinki, Medicum
University of Helsinki, Clinicum
Date: 2015-06-24
Language: eng
Number of pages: 20
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/160383
Abstract: Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16. OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-alpha 2, IFN-gamma, TNF-alpha, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-alpha 2, IFN-gamma and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-alpha 2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-alpha 2, IFN-gamma and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience.
Subject: COLONY-STIMULATING FACTOR
METASTATIC MELANOMA
DENDRITIC CELLS
IN-VIVO
CANCER
IMMUNOTHERAPY
ANTIGEN
RESPONSES
IL-2
PROGRESSION
3111 Biomedicine
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