In Vitro Generation of Cytotoxic T Cells Specific for a Normal Self Protein, PSAShould They Work?
ABSTRACT & COMMENTARY
Synopsis: The authors identified a peptide sequence in the prostate-specific antigen (PSA) that appeared to be "presentable" by class I MHC molecules, and, after months of in vitro selection, generated PSA-specific T cell lines from normal and prostate cancer-bearing people. However, it remains to be seen whether the failure to generate adaptive immunity is the important defect in the failure of the immune system to reject cancers in vivo.
Source: Correale, P, et al. J Natl Cancer Inst 1997;89:293-300.
A typical successful immune response against a foreign pathogen is generally comprised of two phases, an acute phase of antigen non specific activation of innate or natural immunity followed by a more prolonged antigen-specific response by the adaptive immune system. The effector cells of the innate immune system include neutrophils, macrophages, and dendritic cells; contributions are also made by endothelial cells, platelets, and other cell types. The effector cells of the adaptive immune system are T lymphocytes and B lymphocytes. The cells that comprise the natural immune system elaborate a variety of cytokines and enzymes that mediate their function in tissues and, in addition, they elaborate chemokines (chemotactic cytokines) that attract other cell types into the site of injury.
The dominant thinking in tumor immunology for the past 20 years has placed considerable emphasis on the importance of generating a T cell response to the malignancy as the crucial therapeutic goal. Some were initially skeptical that this goal could be achieved, but remarkable new developments over the last four or five years have made it clear that eliciting tumor-specific T cells is feasible. Perhaps the most important conceptual advance was the notion that intracellular proteins could be processed and presented on the surface of a tumor cell and could be recognized as targets by specific cytotoxic T cells. This finding led to the hypothesisfor which considerable experimental data have now been generated in animal modelsthat any mutant protein expressed by the tumor, including proteins mutated in the oncogenic process such as ras and p53, could be legitimate therapeutic targets.
The paper by Correale et al takes this concept to the next step. These authors examined the sequence of PSA, the protease usually restricted to the prostate gland that normally liquefies sperm but is present in the serum in excess quantities in persons with prostate cancer. They found candidate peptide sequences that contained motifs likely to permit their binding to a class I major histocompatibility complex (MHC) protein on the cell surface. They then used peptide-pulsed antigen presenting cells to elicit PSA-specific cell lines from two normal people and one patient with prostate cancer.
After a variable period of in vitro stimulation ranging up to 112 days, cell lines were established that were antigen-specific, MHC-restricted, and were capable of lysing a human prostate carcinoma cell line in vitro. Thus, with appropriately potent in vitro selection, normal individuals and those with prostate cancer can be found to contain T cells specific for a self peptide that is normally not found in the serum. Self-tolerance has been broken in vitro. Of course the major unanswered question is how such heavily selected T cells will perform in vivo. Will they traffic to tumor? Will they traverse endothelial, basement membrane, and tissue barriers to find and destroy tumor cells? Will they function normally in vivo? If the answer is yes, they may become an important component of therapy either through the generation of such cells in vitro or the use of the peptides as vaccines.
COMMENTARY
This paper is important because it confirms that self-tolerance is relative. Self-reactive T cells are present at low levels and can be expanded in vitro under selective pressure. The process of deleting self-reactive clones during ontogeny is imperfect, and, if we are lucky, we may be able to use such rare self-reactive cells to destroy cancer.
Although the prospect of generating tumor-specific cytotoxic T cells is exciting, I have my doubts that this is the answer to cancer treatment. We know that the host is in trouble without T cells, but the same thing can be said for every component of the immune response, both the natural (innate) and adaptive arms. There is an important difference between concluding that T cells are necessary for an antitumor response vs. concluding that they are sufficient for an antitumor response.
It seems to me that a fundamental problem with cancer is the indifference of the immune system to its presence. If you inject some pathogenic bacteria into subcutaneous tissue, you get a florid acute inflammatory response followed by a T-cell response to mop up after the inflammatory cells. Cancers rarely elicit any response from the natural immune system. Even so-called inflammatory breast cancer isn’t really a manifestation of inflammation, but the plugging of lymphatic vessels with growing tumor. The host defense system just does not recognize that a growing cancer represents a danger to the host.
I hope I am wrong, but I think we may be barking up the wrong tree. An enormous amount of effort is being put into eliciting tumor-specific T cells. Yet we have clues both in animal cancer models and in other types of diseases that natural immunity plays a role in an immune response that successfully eliminates disease. The most potent transgenic adjuvant in tumor studies appears to be GM-CSF, a cytokine that activates dendritic cells. None of the T-cell stimulatory cytokines are as effective. T cells must be directed where to go. They are unlikely to find tumor in the course of their meanderings without being directed by signals from macrophages, NK cells, and neutrophils.
Thus, my prediction is that we will hear a few scattered reports of success using heavily in vitro selected tumor-specific T-cell lines, but those successes will not translate into a therapy we can use in our patients. Instead, we shall need to learn how to orchestrate the complex immune response from its first steps. We need to find a way to make tumors appear as dangerous as they really are. We must activate the natural immune system and let that response activate the adaptive immune response, perhaps with a little help from us. The earliest efforts to use antigen-pulsed dendritic cells to elicit in vivo T-cell responses appear to confirm the notion that a response elicited in vivo is more potent than growing millions of cells in vitro and hoping they find their way to tumor in vivo. The next five years should see these concepts and predictions tested.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content