講演1: Regulatory T-cell suppression against self (tumor)-antigen-specific CD8+ T cells

CGCTセミナー
<講演1：18:00～18:40>
Most tumor-associated antigens identified to date are antigenically normal self-constituents. Natural FoxP3⁺CD4⁺ regulatory (Treg) cells, crucial for the maintenance of immunological self-tolerance, hamper effective anti-tumor immune responses in cancer patients. An understanding of the mechanisms of Treg-cell suppression against tumor (self)-antigen-specific T cells is crucial for developing effective cancer immunotherapies. Yet, how Treg cells stably suppress self-(tumor)-antigen-specific CD8⁺ T cells remains obscure. Self-(tumor)-antigen, Melan-A-specific CD8⁺ T cells activated with physiologically-stimulated Treg cells underwent one cell division and stopped further proliferation. These Melan-A-specific CD8⁺ T cells had an anergic phenotype (hypo-proliferative and cytokine hypo-producing upon TCR re-stimulation) identified by expression of CCR7 and co-inhibitory molecules such as CTLA-4. Melan-A-specific CD8⁺ T cells with this anergic phenotype were detected ex vivo in PBMCs from healthy individuals and contributed to the tolerance of self-(tumor)-antigens. This Treg-cell-dependent induction of anergy is likely operating in tumor immunity, indicating the importance of controlling Treg cells to allow the efficient activation of self-(tumor)-antigen-specific CD8⁺ T cells.
To control Treg cells, we attempted to find specific molecules of tumor-infiltrating Treg cells. FoxP3⁺CD4⁺ T cells can be dissected into three subpopulations by the expression levels of FoxP3 and the cell surface molecules CD45RA: FoxP3^loCD45RA⁺ cells (naive or resting Treg cells), FoxP3^hiCD45RA^- cells (effector Treg cells), which are terminally differentiated and highly suppressive; and FoxP3^loCD45RA^- non-Treg cells, which do not possess suppressive activity but can secrete pro-inflammatory cytokines. TILs predominantly contained effector Treg cells, with very low frequencies naive Treg cells and FoxP3⁺ non-Treg cells, compared with the peripheral blood. With depletion of effector Treg cells and subsequent in vitro antigen stimulation, tumor antigen-specific effector T cells were efficiently activated. We propose that selective reduction of effector Treg cells, rather than whole Treg-cell population can augment anti-tumor immune responses without induction of significant autoimmunity.

<講演2：18:40～19:30>
T cell engineering provides a means to rapidly generate therapeutic T cells of any specificity. In oncology, its purpose is to generate potent, tumor-specific T cells that eradicate tumor cells and overcome immune barriers in the tumor microenvironment. T cell engineering is predicated on methods to safely and effectively genetically modify human T lymphocytes, and the transduction of suitable receptors to redirect T cell specificity and function. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T cell activation, and, in the case of second generation CARs, costimulation that is intended to augment the functionality and persistence of engineered T cells. We demonstrated over a decade ago that human T cells engineered with a CAR specific for CD19 eradicated B cell malignancies in mice. We later were the first to report the remarkable complete remission rate obtained with CD19-specific, second generation CARs in patients with chemorefractory, relapsed acute lymphoblastic leukemia. Novel engineering modalities, combining, for example, different costimulatory signals and cytokine release profiles, hold the promise of further enhancing the effectiveness of CAR therapy against other B cell malignancies and solid tumors.