How Cancer Evades the Immune System (7/5/2007)

The researchers studied the expression of genes in mouse tumor models for breast cancer, leukemia, colon cancer, lung cancer (above) and renal cell carcinoma. - Photo Credit: University of Southern California

USC researchers discover a way to determine which genes have been altered in a tumor, enabling it to avoid a body's defenses.

One of the fundamental traits of a tumor – how it avoids the immune system – might become its biggest vulnerability, according to researchers at USC.

Findings indicate that a technique for determining a tumor's "immune signature," demonstrated in human breast and colorectal cancer, could be useful for diagnosing and treating specific cancers.

In the July 1 issue of Clinical Cancer Research, a publication of the American Association for Cancer Research, the researchers describe a means for determining which genes have been altered in a tumor to allow it to escape the body's natural defenses. In time, the researchers believe such analysis could become a routine part of the diagnostic tools available in cancer treatment.

"The implication is that once you know the mechanism by which tumors evade the immune system, you can match that tumor to available therapies," said senior author Alan L. Epstein, professor of pathology at the Keck School of Medicine of USC. "First, we find the genetic changes that allow a tumor to defeat the immune system, then we can apply therapies that compensate for these genetic alterations."

Using real-time PCR, a high-speed gene amplification technique, Epstein and his M.D./Ph.D. student, Rebecca Sadun, screened tumors to understand their immune signatures in order to identify pro-immunity genes that tumors downplay and anti-immunity genes that tumors promote.

According to Epstein, tumors are notorious for demonstrating a broad array of genetic and biological variety. Their immune signatures vary wildly between cancer types, even among subcategories within a particular type of cancer.

The researchers discovered that a small subset of genes can explain immunological behavior. To understand how to characterize an immune signature, the researchers set out to examine the expression of 11 key immunoinhibitory genes, which may be over-produced to allow tumor escape, and 14 immunostimulatory genes, which may be suppressed to slow down the effect of the immune system on the tumor.

The researchers studied the expression of these genes in five mouse tumor models for breast cancer, leukemia, colon cancer, lung cancer and renal cell carcinoma. They then compared two of these immune signatures with corresponding human tumors – eight cases of human ductal carcinoma and 11 cases of colorectal cancer.

Remarkably, the researchers recorded that the immune signatures of each of the human breast cancer cases nearly matched those of mice. In all cases, the researchers saw a suppression of CD83 and CD28, two genes that affect activation of immune cells, and over-production of B7-H4, a gene whose protein product inhibits immune activation.

The human colorectal cancers, however, showed variations in their immune signatures, which researchers saw as an indication of the need to understand the signature for each patient's individual cancer.

"I see it as the beginning stages of personalized medicine, where we develop tactics for treating the unique genetic make-up of a specific tumor," Epstein said. "It becomes even more necessary when we look at all the immunotherapies that are becoming available or are beginning to emerge from research."

In time, Epstein believes, it will be possible to study the immune signatures for most, if not all, forms of cancers. In addition, real-time technology allows for a relatively inexpensive and rapid analysis on equipment available at most medical centers, researchers said.

"For now, we need to better understand the immune signatures for the most common human cancers in order to identify the most important targets for immunotherapy," Epstein said.

The study was funded by the Philip Morris External Research program by Philip Morris USA Inc., Philip Morris International and with support provided by Cancer Therapeutics Laboratories Inc.

Note: This story has been adapted from a news release issued by University of Southern California

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