From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: LAK Cells, Macrophages, and Neutrophils
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6723
Organization: unspecified
Date: Wed, 6 Jan 93 09:04:01 PST

             LAK CELLS, MACROPHAGES, AND NEUTROPHILS 

Chapter 1 Principles of Tumor Immunity: Biology of Cellular Immune 
Responses by John R. Wunderlich and Richard J. Hodes. The book is 
"Biologic Therapy of Cancer" (1991) edited by Vincent T. DeVita, Jr., 
Samuel Hellman and Steven A. Rosenberg; published by J.B. Lippincott 
Company.

Pages 14-15

MHC-DEPENDENT, ANTIGEN-SPECIFIC CYTOTOXIC EFFECTOR CELLS

LYMPHOKINE-ACTIVATED KILLER CELLS

Lymphokine-activated killer (LAK) cells result from culturing 
lymphocytes with relatively high doses of IL-2 [bg: They also occur in 
vivo]. The fundamental characteristic of LAK cells is that they 
selectively lyse a broad spectrum of fresh autologous, syngeneic or 
allogeneic tumor cells in an MHC-independent fashion. They are activated 
cells, derived largely from two sources--NK cells and T cells.

The NK cells are the primary source of LAK activity generated by human 
PBL in response to high doses of IL-2. After exposure to IL-2 for a day 
or more, they are cytotoxic for tumor cells relatively insensitive to 
normal NK-mediated cytotoxicity. The T cells can also generated LAK 
activity. Peripheral blood T cells or IL-2 dependent T-cell lines 
exhibit LAK activity after exposure to relatively high doses of IL-2. It 
is not clear whether LAK cells expressing TCR recognize target-cell 
antigens through MHC-independent TCR binding or whether they express not 
only TCR/CD3, but also target-cell receptors characteristic of NK cells. 
The cytotoxic mechanisms of LAK cells appear to be similar to those of 
NK cells and CTLs.

ACTIVATED MACROPHAGES AND NEUTROPHILS

Activated macrophages, like NK cells and CTLs cultured with relatively 
high doses of IL-2, can be nonspecifically cytotoxic for tumor cells in 
an MHC-independent fashion. Macrophages or monocytes, in contrast to 
CTLs or NK cells, may be phagocytic, express CD68, are commonly 
adherent, and have relatively abundant cytoplasm lacking large 
azurophilic granules. Although they may express CD4, they do not express 
CD2, 3 or 8. They express immunoglobulin Fc receptors and, like NK 
cells, can mediate antibody-dependent cellular cytotoxicity; or like NK 
cells, they can be preferentially cytotoxic for tumor cells upon direct 
contact in the absence of antibody. As with NK cells, cytolysis mediated 
by macrophages extends to virus-infected cells and other forms of 
"altered self," and like NK cells, they do not express immunoglobulin- 
related, antigen-specific receptors or exhibit memory response following 
reexposure of the host to a reactive target.

Macrophages can be activated by numerous factors, including tumor-cell 
contact. But like NK cells, a macrophage antibody-independent triggering 
site that binds to a tumor cell-surface ligand has not been identified. 
Bacterial products, such as lipopolysaccharides (LPS), are among the 
most potent sources of macrophage activators. Another source of 
activation was originally referred to as macrophage activating factor 
(MAF), contained in the supernatants from stimulated T cells. 
Interferon-gamma (IFN-gamma) has been identified in these supernatants, 
and when purified, it is a strong activating agent, particularly in 
concert with an LPS. Other MAFs that activate macrophages for tumor-cell 
killing are granulocyte-macrophage colony-stimulating factor (GM-CSF) 
and CSF-1. Not all activating agents support all macrophage mechanisms 
for antitumor activity.

Destruction of tumor cells or inhibition of their growth by activated 
macrophages is mediated extracellularly by one or more of a variety of 
mechanism stimulated by macrophage binding to tumor cells. The binding 
appears to be receptor mediated. Macrophages rarely endocytose tumor 
cells. Cytotoxic mechanism include antibody-independent and -dependent 
cytolysis and separate processes associated with inhibition of DNA 
synthesis, or cytostasis. Numerous cytotoxic mediators have been 
implicated, including cytolytic proteases, TNF-alpha and related 
factors, IFN-alpha, gamma, IL-1, reactive oxygen intermediates such as 
H(2)O(2), arginase, thymidine, and lysosomal enzymes. Some of the 
mediators, such as TNF-alpha, bind to cell-surface receptors on target 
cells; however, the degree of target-cell susceptibility does not 
correlate with the number of receptors. Pore-forming proteins have not 
been identified. A 26-kD cytotoxic form of TNF-alpha has been found 
attached to the membranes of monocytes, which could contribute to 
localized cytotoxicity. The 26-kD TNF-alpha appears to be the precursor 
of a 17-kD TNF-alpha that is secreted. The secreted form of TNF-alpha 
may also act only locally, unless there is more generalized monocytes 
activation, such as in septicemia.

Of note, the in vivo effects of cytokines, in general, can be very 
complex, because often they can (1) have one effect on some target cells 
but different effects on other cells, (2) induce or inhibit the 
production of other cytokines, and (3) antagonize or enhance the actions 
of other cytokines.

The antitumor cytotoxic activity of neutrophils has not been as widely 
studied as that of the other effector cells; however, there are a 
variety of report that neutrophils can mediate tumor killing by either 
direct contact or by an antibody-dependent mechanism similar to that of 
macrophages and NK cells. Cytotoxicity generally requires neutrophil 
activation. Supernatants from concanavalin A-activated lymphoid cells, 
IFN-gamma, TNF-alpha, and TNF-beta are potent activators of neutrophils. 
Reactive oxygen products and lysosomal enzymes have been implicated in 
the killing process.
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