A Coreceptor-Independent Transgenic Human TCR Mediates Anti-Tumor and Anti-Self Immunity in Mice

Abstract

Recent advancements in T cell immunotherapy suggest that T cells engineered with high affinity T cell receptors (TCR) can offer better tumor regression. However, whether a high affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope reactive, CD8 independent, high affinity TCR isolated from MHC class-I restricted CD4+ T cells obtained from tumor infiltrating lymphocytes of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2 restricted TCR was positively selected on both CD4+ and CD8+ single-positive (SP) cells. However, when the TCR transgenic mouse was developed with an HLA-A2 background, the transgenic TCR was primarily expressed by CD3+CD4-CD8- double-negative (DN) T cells. TIL 1383I TCR transgenic CD4+, CD8+ and CD4-CD8- T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo. Furthermore, the HLA-A2+/human tyrosinase TCR double transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high affinity TIL 1383I TCR alone in CD3+ T cells is sufficient to control the growth of murine and human melanoma and the presence or absence of CD4 and CD8 co-receptors had little effect on its functional capacity.

Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent

“…s3A). To confirm our results in a second model, we used the h3T TCR transgenic mouse, whose T cells recognize tyrosinase in an HLA-A2-restricted manner (37). h3T T cells activated in the presence or absence of IL-12 showed similar persistence when transferred into irradiated WT B6 or HLA-A2 transgenic mice (Fig.…”

“…IL-15 −/− mice were purchased from Taconic (Hudson, NY). H3T TCR transgenic mice were generated as previously described (32). Pmel-1 mice were maintained by crossing a pmel-1 (male) to a Thy1.1 (female) generating hemizygous offspring.…”

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

“…A comparative determination of the anti-tumor property between Th1, Th17 or Th1/17 cells differentiated ex vivo using melanoma epitope tyrosinase reactive CD4 + T cells obtained from h3T TCR transgenic mice (Mehrotra et al, 2012), showed that adoptive transfer of hybrid Th1/17 cells exhibit superior tumor control as compared to Th1, Th17 (Figure 2A) or even Th17 IL1β+TGFβ cells (Figure S2A). Administering anti-IFNγ or anti-IL17 antibody to the recipient mice along with ACT showed that IL17 neutralization had minimal effect on B16 tumor progression, at least during the initial three weeks, whereas blocking of IFNγ completely diminished the anti-tumor potential of Th1/17 cells (Figure 2B).…”

“…CD38KO-IFNγ Thy1.1 knock-in mice, HLA-A2 + -Rag −/− mice and Pmel-IFNγ −/− mice were developed in the lab. Melanoma epitope tyrosinase reactive HLA-A2 restricted TCR transgenic mouse (referred as h3T in the text) was developed in the lab and reported earlier (Mehrotra et al, 2012). Animals were maintained in pathogen-free facilities and experimental procedures were approved by Institutional Animal Care and Use Committees of Medical University of South Carolina, Charleston.…”

Reducing CD73 Expression by IL1β-Programmed Th17 Cells Improves Immunotherapeutic Control of Tumors

“…Development of h3T transgenic mouse bearing TCR reactive to the human tyrosinase 368–376 (YMDTMSQV) epitope has been described recently (14). OT-II-GFP-FoxP3 mice co-expressing EGFP and FoxP3 were kind gift from Dr. C. Vasu, MUSC.…”