FOUR KEY FINDINGS: The immune system eliminates some
tumor cells, changes the characteristics of others.
1. Lymphocytes and IFN gamma help prevent formation of
chemically induced tumors
Schreiber's team first examined whether mice
lacking lymphocytes developed tumors when exposed to a chemical
carcinogen. To do so, they developed a strain of mice that definitively
lacked functional lymphocytes. This was accomplished by inactivating
a gene found in all lymphocytes, RAG2.
They then injected the chemical carcinogen MCA
into a group of mice lacking RAG2 and into a group of normal mice.
Only 19 percent of normal mice developed tumors, in contrast with
58 percent of RAG2-deficient mice.
In previous studies, the group examined the effect
of MCA on mice lacking either the receptor for IFN gamma or one of the
proteins required for the receptor to function, Stat1. Roughly half
of these mice also developed tumors.
In their current study, the researchers also
generated mice with two disrupted genesthe gene for RAG2 and the
gene for Stat1. When these doubly-deficient mice were injected with
MCA, 72 percent of them developed tumors. Statistically, this was
not greater than the incidence of tumors in mice that lacked just
one gene or the other. Therefore, the team concluded that RAG2 and
the IFN gamma receptor have overlapping roles.
We think the two are potentially part of the
same mechanism but represent different steps in the process, explains
Schreiber. IFN gamma makes tumor cells expose themselves to the immune
system. After seeing the abnormal proteins in the tumor, the lymphocytes
eliminate the tumor cells.
2. Lymphocytes and IFN gamma help prevent formation of
spontaneous tumors
Only some human tumors can be directly blamed
on chemical carcinogens. Often, tumors develop spontaneously, without
any apparent trigger. So Schreiber and colleagues examined whether
lymphocytes and Stat1 contribute to the natural development of tumors
in the absence of a carcinogen.
Again, they studied three groups of micenormal,
RAG2-deficient, and those deficient in both RAG2 and Stat1.
After 15 months, two of 11 normal mice had noncancerous
tumors and the rest were tumor-free. On the other hand, all 12 RAG2-deficient
mice had developed tumors, half of which were cancerous.
Particularly surprising was the fact that mice
lacking both RAG2 and Stat1 seemed to get very sick very quickly.
All 11 doubly-deficient mice developed tumors well before 15 months.
Moreover, six developed cancerous tumors in the mammary glands.
This type of cancer rarely occurs in RAG2-deficient mice or in young
mice lacking the IFN gamma receptor.
At first glance, the higher threat of developing
spontaneous tumors in doubly-deficient mice seems to contradict
the first finding that mice lacking both genes are not at a significantly
greater risk of developing chemically induced tumors. But IFN gamma also
plays a part in non-immune responses. According to Schreiber, while
the roles of lymphocytes and IFN gamma overlap, IFN gamma also might prevent
tumor formation via mechanisms not involving the immune system.
3. Even a healthy immune system only catches some
tumorsthose that escape detection pose a greater threat
The first two findings show that both IFN gamma and
lymphocytes interact with one another to protect individuals from
cancer development. That's the good news.
But there's also bad news.
Tumors that developed in normal mice due to injection
of MCA were later transplanted into healthy mice. The tumors continued
to grow. Tumors from RAG2-deficient mice also were transplanted
into healthy mice. Eight out of 20 of these were rejected.
Apparently, the immune systems in healthy, carcinogen-free
mice were better equipped to recognizeand rejecttumor cells that
developed in RAG2-deficient mice (in the absence of a healthy immune
system) than tumor cells that had developed in mice with intact
lymphocytes.
As a result of protecting the body, the immune
system paradoxically favors the outgrowth of tumors that are less
likely to be recognized and killed by the immune system, Schreiber
says. It's a Ôsurvival of the fittest' scenario that works against
the host.
His immunoediting theory may explain this selective
protection. If immunoediting is always occurring, it can have multiple
outcomes, he explains. If you're lucky, the outcome is protection.
But if you're unlucky, transformed tumor cells might alter themselves
so the immune system can pick out only a few. The others continue
growing.
4. TAP1 can flag tumors, making them more visible
to the immune system
Some tumors that escape immune detection appear
to have low levels of a protein called TAP1. So the scientists added
this protein to tumors before transplanting them into healthy mice.
This, they hoped, would trick the immune system and allow for easier
identification of dangerous cells.
When highly aggressive tumors such as those that
managed to develop in mice with a healthy immune system were transplanted
into healthy mice, they grew in an extremely rapid manner. However,
when these tumors first were tagged with TAP1 before being transplanted,
they were rejected.
When tagged tumors were transplanted into RAG2-deficient
mice, they still went unnoticed. Thus, TAP1 facilitated tumor detection
and elimination only in the presence of a healthy immune system.
We showed that if a tumor is forced to reveal
itself to the immune system, it often is rejected, Schreiber explains.
We think that a tagged tumor could be used to train the immune
system to reject others like it. This is very exciting because it
indicates that immunotherapy has a significant potential use even
for the treatment of tumors that are altered by the immunoediting
process.
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