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.""""""""
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.
|Chiuzan, Cody; Garrett-Mayer, Elizabeth; Nishimura, Michael (2018) An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials. Stat Biopharm Res 10:185-195|
|Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita et al. (2018) CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab 27:85-100.e8|
|Jacks, Ramiah D; Keller, Taylor J; Nelson, Alexander et al. (2018) Cell intrinsic characteristics of human cord blood naïve CD4T cells. Immunol Lett 193:51-57|
|Foley, Kendra C; Nishimura, Michael I; Moore, Tamson V (2018) Combination immunotherapies implementing adoptive T-cell transfer for advanced-stage melanoma. Melanoma Res 28:171-184|
|Chatterjee, Shilpak; Chakraborty, Paramita; Daenthanasanmak, Anusara et al. (2018) Targeting PIM Kinase with PD1 inhibition Improves Immunotherapeutic Antitumor T-cell Response. Clin Cancer Res :|
|Moore, Tamson; Wagner, Courtney Regan; Scurti, Gina M et al. (2018) Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells. Cancer Immunol Immunother 67:311-325|
|Johnson, C Bryce; May, Bennett R; Riesenberg, Brian P et al. (2018) Enhanced Lymphodepletion Is Insufficient to Replace Exogenous IL2 or IL15 Therapy in Augmenting the Efficacy of Adoptively Transferred Effector CD8+ T Cells. Cancer Res 78:3067-3074|
|Spear, Timothy T; Wang, Yuan; Smith Jr, Thomas W et al. (2018) Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells. Mol Ther 26:996-1007|
|Wrangle, John M; Velcheti, Vamsidhar; Patel, Manish R et al. (2018) ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol 19:694-704|
|Spear, Timothy T; Foley, Kendra C; Garrett-Mayer, Elizabeth et al. (2018) TCR modifications that enhance chain pairing in gene-modified T cells can augment cross-reactivity and alleviate CD8 dependence. J Leukoc Biol 103:973-983|
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