CTLs and spontaneous tumors

The majority of human cancers are spontaneous tumors that are not of blood-cell origin, and it has been proposed that killer T cells might provide surveillance against these cancers. Let’s try to evaluate this possibility.

Imagine that a heavy smoker finally accumulates enough mutations in the cells of his lungs to turn one of them into a cancer cell. Remember, it only takes one bad cell to make a cancer. And let’s suppose that because of these mutations, this cell expresses proteins that could be recognized as foreign by CTLs. Now let me ask you a question: where are this man’s naive T cells while the tumor is growing in his lung? That’s right. They are circulating through the blood, lymph, and secondary lymphoid organs. Do they leave this circulation pattern to enter the tissues of the lung? No, not until after they have been activated.

So right away, in terms of immune surveillance, we have a “traffic problem”. To make self tolerance work, Mother Nature set up the traffic system so that naive T cells don’t get out into the tissues where they might encounter self antigens that were not present in the thymus during tolerance induction. As a result, it’s unlikely that virgin T cells ever would “see” tumor antigens expressed in the lung – because they just don’t go there. What we have here is a serious conflict between the need to preserve tolerance of self (and avoid autoimmune disease) and the need to provide surveillance against tumors that arise, as most tumors do, out in the tissues. And tolerance wins.

Now, sometimes virgin T cells do disobey the traffic laws and wander out into the tissues. So you might imagine that this kind of adventure could give some T cells a chance to look at the tumor that’s growing in this guy’s lung, and be activated. But wait! What is required for T cell activation? First of all, killer T cells must recognize antigens which are produced within a cell and presented by class I MHC molecules on the surface of that cell. This means that the tumor cell itself must do the antigen presentation. So far, so good. However, CTLs also require co-stimulation from the cell that presents the antigen. Is this lung tumor cell going to provide that costimulation? I don’t think so! This isn’t an antigen presenting cell, after all. It’s a plain old lung cell, and lung cells usually don’t express co-stimulatory molecules like B7. Consequently, if a renegade, virgin CTL breaks the traffic laws, enters the lung, and recognizes a tumor antigen displayed by the tumor cell, that CTL most likely will be anergized or killed – because the tumor cell cannot provide the co-stimulation the CTL needs for survival.

Again we see a conflict between tolerance induction and tumor surveillance. The two-key system of specific recognition plus co-stimulation was set up so that T cells which recognize self antigens out in the tissues, but which do not receive proper co-stimulation, will be anergized or killed to prevent autoimmunity. Unfortunately, this same two-key system makes it very difficult for CTLs to be activated by tumor cells that arise in the tissues. So the bottom line is that a CTL would have to perform “unnatural acts” to be activated by a tumor out in the tissues: it would have to break the traffic laws, and somehow avoid being anergized or killed. This could happen, of course, but it would be very inefficient compared to the activation of CTLs in response to, for example, a viral infection.

Another possible scenario is that cancer cells from the primary tumor might metastasize to a lymph node, where T cells could be activated. However, by the time this happens, the original tumor probably will have become quite large. Even a tumor that weighs only about half an ounce will contain more than 10 billion cancer cells – more cells than there are people on our planet! This poses a major problem for immune surveillance, because cancer cells usually mutate like crazy, and with so many cells mutating, it is likely that some of these mutations will prevent recognition or presentation of tumor antigens. For example, the gene encoding the tumor antigen itself can mutate so that the tumor antigen no longer can be recognized by activated CTLs, or no longer will fit properly into the groove of an MHC molecule for presentation. In addition, tumor cells can mutate so that they stop producing the particular MHC molecules that CTLs are restricted to recognize. This happens quite frequently: about 15% of the tumors that have been examined have lost expression of at least one of their MHC molecules. Also, genes that encode the TAP transporters can mutate in a tumor cell, with the result that tumor antigens will not be efficiently transported for loading onto class I MHC molecules. Indeed, a tumor cell’s high mutation rate is its greatest advantage over the immune system, and usually keeps these cells one step ahead of surveillance by CTLs. So even when it occurs, CTL surveillance is usually a case of “too little, too late.”

Дата добавления: 2015-06-04