CD28 Costimulation Overcomes Transforming Growth Factor-β–Mediated Repression of Proliferation of Redirected Human CD4+ and CD8+ T Cells in an Antitumor Cell Attack

Abstract

The T-cell-mediated antitumor immune response is frequently repressed in the tumor environment by an immunologic barrier, the predominant mediators of which are thought to be interleukin-10 (IL-10) and transforming growth factor-B (TGF-B). We explored the effect of these cytokines on the individual T-cell effector functions on antigen engagement during an antitumor cell attack. Isolated CD4 + and CD8 + T cells were antigen-specifically redirected toward carcinoembryonic antigen (CEA)-positive tumor cells by expression of a recombinant T-cell receptor (immunoreceptor), which triggers T-cell activation via CD3Z on binding to CEA. Immunoreceptor-activated T cells secrete IFN-;, proliferate, and lyse CEA + but not CEA À tumor cells. Whereas IL-10 has no direct effect on immunoreceptor-triggered effector functions, TGF-B represses proliferation of both CD4 + and CD8 + T cells but neither IFN-; secretion nor specific cytolytic activities. CD28 costimulation, however, overcomes TGF-B-mediated repression in T-cell proliferation. Consequently, T cells redirected by a combined CD28-CD3Z signaling immunoreceptor are largely resistant to TGF-B-mediated repression. This is reflected in vivo by a more pronounced antitumor activity of T cells against TGF-B-secreting tumors when redirected by a costimulatory CD28-CD3Z than by a CD3Z signaling immunoreceptor. [Cancer Res 2007;67(5):2265-73]

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

“…7 CD28-CD3z CAR signalling moreover counteracts transforming growth factor-b1-mediated repression in T-cell proliferation. 10 Both sustained survival and increased amplification result in a prolonged redirected T-cell response and in an improved antitumor attack, making second-generation CARs favorable for clinical use. [11][12][13] In physiological activation of naïve T cells, CD28 recruitment by B7 engagement sustains formation of the immunological synapse, thereby lowering the antigen threshold and increasing T-cell activation.…”

Eradication of melanomas by targeted elimination of a minor subset of tumor cells

“…Redirected cytotoxic T cells mediate target cell lysis predominantly in a granzyme-dependent manner (11). By immunostaining tumors in mice treated with HMW-MAA redirected T cells, we thus revealed that HMW-MAA + melanoma cells took up granzyme B as did CD20 + melanoma cells after a CD20-specific T-cell attack (Fig.…”

Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells

“…In addition, with respect to the immunosuppressive nature of the tumor milieu, TGF-, a candidate suppressive cytokine produced by tumor cells, represses the proliferation of both CD4 + and CD8 + CAR-T cell subsets but does not repress IFN- secretion of CAR-T cells or specific CAR-T cell cytolytic activity. CD28 co-stimulation overcomes the TGF--mediated repression of T-cell proliferation (Koehler et al, 2007), reflected by a more pronounced killing of tumor cells. Furthermore, in a CD28-CD3 CAR, deletion of the lymphocyte-specific protein kinase (LCK) binding site in the CD28 endodomain could improve anti-tumor activity of the CAR-T cells even though Treg cells are present in the tumor lesion (Kofler et al, 2011).…”