In this study, we postulate that the failure of adoptive T cell therapy against recurrent melanoma may be based in part on the CD8+ T cell susceptibility to tumor-Induced suppression). Here, we show that TCR costimulation by NKG2D signaling in CD8+ T cells results in resistance to suppression by TGF-B, augmented formation of cells resembling central memory and enhanced cytolytic function. We established a direct correlation between these traits and NKG2D co-stimulation, through upregulation of a recently described negative regulator of TGF-B signaling in T cells, termed regulator of G-protein signaling 3 (RGS3), and repression of T-bet expression. We also found that memory CD8+ T cells express high levels of RGS3 and are resistant to tumor-induced suppression. Thus, we propose to study how NKG2D signaling in tyrosinasereactive TCR-transduced (TIL 13831) effector and memory CD8+ T cells affects their resistance to suppression. Hypothesis 1: If NKG2D signaling in CD8+ T cells enhances cytolytic function, augments RGS3 expression and represses T-bet, then NKG2D-co-stimulated CD8+ T cells will be highly functional against tumors by acquisition of resistance to TGF-P-mediated suppression and augmented formation of MPECs and long-term T cell memory. Hypothesis 2: If the characteristic functional response by central memory cells is faster, stronger, of longer duration and resistant to TGF-B;then TCR-transduced CD8+ memory T cells will result in cells with similar functional abilities, and if not, then responses and resistance will be recovered by NKG2D engagement.
In Specific Aim 1, we will determine how NKG2D co-stimulatory signaling in TCR transduced CD8+T cells against melanoma affects their resistance to tumor-induced suppression, short-lived effectors and memory-progenitor effector cells formation and effector/memory development.
In Specific Aim 2, we will determine how NKG2D signaling in CD8+ memory T cells serving as recipients of TCR TIL 13831 affects their resistance to tumor-induced suppression, persistence and function. We will also study the effects of NKG2D signaling in human TCR-transduced CD8+ T cells prior and after transfer into patients participating in the clinical trial """"""""ACT with TCR (TIL 1383l)-transduced T cells against melanoma.""""""""

Public Health Relevance

The results obtained from the proposed study are expected to help in understanding how changes in the quality of co-stimulatory stimuli (NKG2D signal) change the balance of CD8+ T cell resistance/susceptibility to tumor-induced suppression. Thus, in order to aid in the enhancement of anti-melanoma ACT, we propose to study the effects of NKG2D engagement on effector and memory CD8+ T cells that are recipients ofthe tyrosinase-reactive TCR (TIL 13831) for the treatment of melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154778-04
Application #
8745150
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$226,064
Indirect Cost
$69,830
Name
Loyola University Chicago
Department
Type
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Spear, Timothy T; Wang, Yuan; Foley, Kendra C et al. (2017) Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells. Cancer Immunol Immunother 66:1411-1424
Foley, Kendra C; Spear, Timothy T; Murray, David C et al. (2017) HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer. Mol Ther Oncolytics 5:105-115
Spear, Timothy T; Callender, Glenda G; Roszkowski, Jeffrey J et al. (2016) TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol Immunother 65:293-304
Banerjee, Anirban; Thyagarajan, Krishnamurthy; Chatterjee, Shilpak et al. (2016) Lack of p53 Augments Antitumor Functions in Cytolytic T Cells. Cancer Res 76:5229-5240
Blevins, Sydney J; Pierce, Brian G; Singh, Nishant K et al. (2016) How structural adaptability exists alongside HLA-A2 bias in the human ?? TCR repertoire. Proc Natl Acad Sci U S A 113:E1276-85
Klarquist, Jared; Eby, Jonathan M; Henning, Steven W et al. (2016) Functional cloning of a gp100-reactive T-cell receptor from vitiligo patient skin. Pigment Cell Melanoma Res 29:379-84
Hellman, Lance M; Yin, Liusong; Wang, Yuan et al. (2016) Differential scanning fluorimetry based assessments of the thermal and kinetic stability of peptide-MHC complexes. J Immunol Methods 432:95-101
Spear, Timothy T; Nagato, Kaoru; Nishimura, Michael I (2016) Strategies to genetically engineer T cells for cancer immunotherapy. Cancer Immunol Immunother 65:631-49
Sandri, Sara; Bobisse, Sara; Moxley, Kelly et al. (2016) Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies. Cancer Res 76:2540-51

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