Enhancement of APC Activity Can Modulate Tumor Immunity

Mouse dendritic cells cultured in GM-CSF and incubated with tumor fragments, then reinfused into the mice, have been shown to activate both TH cells and CTLs specific for

gene

gene

Tumor cell transfected —> CTL activation with B7 gene

Tumor cell transfected —> CTL activation with B7 gene

Tumor destruction

GM-CSF CTL-P

Th IL-2

Dendritic cell presents tumor antigen

GM-CSF CTL-P

GM-CSF gene

GM-CSF gene

Enhancement Apc Activity

Tumor cell transfected with GM-CSF gene

T Dendritic cells

Th IL-2

Dendritic cell presents tumor antigen

CTL-P

Tumor cell transfected with GM-CSF gene

FIGURE 22-11

T Dendritic cells

activation

Tumor destruction

Use of transfected tumor cells for cancer immunotherapy. (a) Tumor cells transfected with the B7 gene express the co-stimulatory B7 molecule, enabling them to provide both activating signal (1) and co-stimulatory signal (2) to CTL-Ps. As a result of the combined signals, the CTL-Ps differentiate into effector CTLs, which can mediate tumor destruction. In effect, the transfected tumor cell acts as an antigen-presenting cell. (b) Transfection of tumor cells with the gene encoding GM-CSF allows the tumor cells to secrete high levels of GM-CSF. This cytokine will activate dendritic cells in the vicinity of the tumor, enabling the dendritic cells to present tumor antigens to both TH cells and CTL-Ps.

the tumor antigens. When the mice were subsequently challenged with live tumor cells, they displayed tumor immunity. These experiments have led to a number of approaches aimed at expanding the population of antigen-presenting cells, so that these cells can activate TH cells or CTLs specific for tumor antigens.

One approach that has been tried is to transfert tumor cells with the gene encoding GM-CSF. These engineered tumor cells, when reinfused into the patient, will secrete GM-CSF, enhancing the differentiation and activation of host antigen-presenting cells, especially dendritic cells. As these dendritic cells accumulate around the tumor cells, the GM-CSF secreted by the tumor cells will enhance the presentation of tumor antigens to TH cells and CTLs by the dendritic cells (Figure 22-11b).

Another way to expand the dendritic-cell population is to culture dendritic cells from peripheral-blood progenitor cells in the presence of GM-CSF, TNF-a, and IL-4. These three cytokines induce the generation of large numbers of dendritic cells. There is some hope that, if these dendritic cells are pulsed with tumor fragments and then reintroduced into the patient, they can activate TH and TC cells specific for the tumor antigens. Whether these hopes are justified will be determined by further investigation.

A number of adjuvants, including the attenuated strains of Mycobacterium bovis called bacillus Calmette-Guerin (BCG) and Corynebacterium parvuum, have been used to boost tumor immunity. These adjuvants activate macrophages, increasing their expression of various cytokines, class II MHC molecules, and the B7 co-stimulatory molecule. These activated macrophages are better activators of TH cells, resulting in generalized increases in both humoral and cell-mediated responses. Thus far, adjuvants have shown only modest therapeutic results.

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