In our original studies, we first described the ability to generate MHC class I restricted CD4+ T cells by retrovirally transduced normal T cells with MHC class I restricted TCR genes. We subsequently showed that if the TCR had sufficient affinity, the resulting MHC class 1 restricted CD4+ T cells could recognize physiologic levels of antigen expressed by tumor cells. Therefore, these novels T cells could augment the anti-tumor immune response by helping to prime the host immune response in tumor lesions. They could also promote the persistence and function of adoptively transferred CD8+ T cells. However, nothing is known about the biology of TCR transduced CD4+ T cells in vivo and their impact on the CD8+ T cells in vitro or in vivo. We have preliminary data that shows this novel population actually inhibits CD8+ T cell priming which would be contrary to their desired function. The goal of this project is to acquire a better understanding ofthe role of MHC class 1 restricted CD4+ T cells in anti-tumor immunity. Our central hypothesis is that MHC class I restricted, TCR transduced CD4+ T cells can be made to augment the antitumor immune response by CD8+ T cells. We predict this will occur by inducing them to become potent Th cells capable of licensing DC to prime CD8+ T cells in vitro. We further predict that MHC class I restricted, TCR transduced CD4+ T cells can be made promote the persistence and function of TCR transduced CD8+ T cells in vivo. These hypotheses/predictions will be tested using a combination of mouse and human CD4+ T cells transduced to express the TIL 13831 TCR. These TCR transduced CD4+ T cells, which recognize the tyrosinase:368-376 epitope presented by HLA-A2, will be compared to their normal mouse or human counterparts for their ability secrete cytokines, license DC to prime/activate naive and TCR transduced CD8+ T cells, and mediate tumor regression in vivo.
This Project will study the biology of TCR transduced cells that are engineered to be MHC class I restricted. This novel T cell population could help activate the host immune response against tumor antigens and maintain the persistence of adoptively transferred CD8+ T cells in vivo. Using a combination of mouse and human models, we will determine how to apply the biology we learn to improve the effectiveness of TCR transduced T cells in cancer patients.
|Wang, Yuan; Singh, Nishant K; Spear, Timothy T et al. (2017) How an alloreactive T-cell receptor achieves peptide and MHC specificity. Proc Natl Acad Sci U S A 114:E4792-E4801|
|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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