for Rick..see, Ian and I are looking out with you..[edit1..all of us are..in no small part due to knowledge you share on a daily basis]
edit2 content.nejm.org
above pdf=corresonding paper
Immune Response as a Biomarker for Cancer Detection and a Lot More
Olivera J. Finn, Ph.D.
Volume 353:1288-1290 September 22, 2005 Number 12Next
the American Cancer Society inaugurated a yearly report on guidelines for cancer detection. The latest update, published in 2005,1 is identical to the previous versions in its recommendation regarding screening techniques that have not changed in decades. An especially striking feature of the recommendations is the continued absence of any mention of laboratory tests that should be readily available, considering the explosion of knowledge in cancer biology, molecular biology, genetics, and immunology. The scientific literature is full of articles heralding the potential of genomics,2 proteomics,3 metabolomics,4 and other "omics" for the improvement of the diagnosis, treatment, and prognosis of cancer, but ways of making these methods clinically applicable are not being developed fast enough. The only laboratory test for cancer screening on the society's list is the test for prostate-specific antigen (PSA). The PSA level can be useful in monitoring disease progression or recurrence, but as a screening test it can lead to overdiagnosis and unnecessary biopsies.5,6 The PSA problem speaks loudly to the need for better tests for prostate cancer and other cancers.
The search for new biomarkers for use in the diagnosis of cancer entails characterizing one or a few proteins produced by cancer cells and establishing assays with high specificity and sensitivity for cancer or defining a cancer fingerprint on the basis of a larger set of proteins, many of which are known only as unique peaks on a mass spectrogram. Exemplifying the first approach are techniques described in two recent publications on proteins that are specific to prostate cancer and that are potentially superior to PSA in their ability to discriminate between cancer and benign disease.7,8 The second approach uses advances in protein analysis that allow proteomic profiling that distinguishes patients with cancer from healthy persons. In one recent study, for example, serum samples from men with elevated PSA levels were evaluated with the use of high-performance, hybrid quadrupole time-of-flight mass spectrometry to generate proteomic profiles with the potential to distinguish between men who should undergo prostate biopsy and those who should not.9 In this work, high-resolution mass spectrums that were analyzed with a pattern-recognition bioinformatics tool yielded ion signatures that distinguished with 100 percent sensitivity and 67 percent specificity between men with an elevated PSA level due to benign conditions and those with prostate cancer.
We can expect that these new approaches will yield some serum proteins or protein patterns with specificity for a particular cancer type and others that are common to all cancers. These methods, however, are still best at detecting tumors that are large enough to be diagnosed clinically. To make a difference, especially in improving the outcome of treatment, screening methods must be able to detect very early tumors — even premalignant lesions. This means that the tests must have adequate sensitivity and specificity to detect very low levels of cancer proteins.
There is no detection instrument that rivals the sensitivity and specificity of the immune system. Hence, one promising approach to the early detection of cancer is to look not for cancer but for the immune response to cancer. There is clear evidence that the immune system, in addition to defending us against pathogens, is also on guard against other threats, including cancer.10 Many tumor antigens that are currently targets for therapy have been identified with the use of the patient's own anticancer antibodies or T cells.10,11,12 Since the immune response is generated locally, very small amounts of tumor-specific or tumor-associated proteins that originate in only a few tumor cells — so few that they would be undetectable by any other means — can be concentrated and processed by antigen-presenting cells and displayed to lymphocytes in the lymph node that drains the site of a developing tumor. Antibodies and T cells that are generated locally in response to these antigens enter the circulation, where they can be easily detected. The immune system is especially well adapted for the detection of very low levels of antigen, and it responds to these minute amounts of antigen by generating very-high-affinity T cells and antibodies. Thus, the Achilles' heel of other detection methods — an inability to detect low levels of cancer proteins — is the strength of immune-based mechanisms that function optimally with limited doses of antigen.
In this issue of the Journal, Wang et al. report work that takes advantage of antitumor immunity and propose a method for the detection of prostate cancer on the basis of the patient's antitumor-antibody repertoire, which the investigators term "autoantibody signatures."13 They derived these signatures by reacting serum samples from patients with prostate cancer and healthy controls with a phage-display library made with complementary DNA (cDNA) obtained from prostate cancer tissues. Through carefully performed selection and phage-enrichment procedures followed by protein-microarray analysis (as well as testing of a large number of samples divided into training and validation sets), they arrived at a 22-phage-peptide detector set that was specifically recognized by the serum of patients with prostate cancer and not by that of controls, with a significant additional discriminative power over PSA testing (P<0.001). Of the phages in the detector set, four are known proteins with deregulated expression in prostate cancer, whereas the others are unidentified and may be "mimotopes," or stretches of amino acids that mimic the antigen for which the antibody is specific.
Considering that some of the most profound changes in malignant cells are due to aberrant protein glycosylation,14 many of the tumor-specific antibodies that Wang et al. found might be directed against cancer-specific carbohydrates that are mimicked by the phage-displayed peptides. If the mimotope hypothesis is true, the definition of antibody signatures for cancer diagnosis may not require new phage libraries derived from the cDNA of tumor tissues; libraries displaying random peptides could work just as well and might be more practical. This alternative approach has been used to "fingerprint" the circulating repertoire of antibodies from patients with prostate cancer and to isolate a mimic of a potentially useful diagnostic and prognostic marker of the tumor.15
Of interest to tumor immunologists is the fact that the discriminative antibodies in the study reported by Wang et al. and in several other studies are of the IgG isotype, which is dependent on helper T cells and thus is an indication of a comprehensive antitumor immune response. In addition to the diagnostic potential of tumor-specific antibodies, there is the opportunity to seek tumor-specific T cells in the patient's blood. However, the requirement that screening tests be easy, practical, and inexpensive favors antibody-based assays for use in clinical laboratories, leaving the more complicated and labor-intensive T-cell assays to research laboratories.
Antibodies and T cells are effector arms of the immune response and have the capacity not only to recognize the tumor but also to eliminate it. As we continue to learn more about the repertoire of antitumor antibodies and T cells, especially about the differences between a tumor-specific response and a tumor-rejection response, we may be able to design diagnostic tests on the basis of one antibody signature or fingerprint and use another antibody signature as a prognostic marker. One set of antibodies may tell us that a tumor is developing (diagnosis), whereas another set might tell us that the tumor has been or is likely to be destroyed (prognosis). For example, a recent study of antibodies against defined tumor antigens in serum specimens from 527 patients with cancer and 346 controls found that a panel of only seven antigens was sufficient for the diagnosis of cancer.16 Among the antigens was cyclin B1, a target for both cellular and humoral immunity.17,18 This finding is important because antibodies against cyclin B1 may be a marker for premalignant lesions.18 Another tumor antigen in the diagnostic panel was p53, an often mutated or inactivated tumor-suppressor gene product. Because p53 mutations occur early in cancer development, anti-p53 antibodies could be useful in detecting early cancers, as was shown in workers who had been exposed to asbestos and were at high risk for cancer.19
Assays for early cancer detection that are based on the antitumor immune response provide important information as well as an opportunity to exploit that response for treatment. Perhaps in the future, a set of cancer proteins will be arrayed on a diagnostic chip to be used for early cancer detection. The same set of proteins will also be formulated into a cancer vaccine and delivered to the doctor's office, ready to boost the patient's natural immunity against the cancer.
Source Information
From the Department of Immunology, University of Pittsburgh School of Medicine, and the University of Pittsburgh Cancer Institute — both in Pittsburgh.
References
1. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer, 2005. CA Cancer J Clin 2005;55:31-44, 55. [Abstract/Full Text]
2. Weber BL. Cancer genomics. Cancer Cell 2002;1:37-47. [CrossRef][ISI][Medline]
3. Wulfkuhle JD, Liotta LA, Petricoin EF. Proteomic applications for the early detection of cancer. Nat Rev Cancer 2003;3:267-275. [CrossRef][ISI][Medline]
4. Fan TW, Lane AN, Higashi RM. The promise of metabolomics in cancer molecular therapeutics. Curr Opin Mol Ther 2004;6:584-592. [ISI][Medline]
5. Stamey TA, Caldwell M, McNeal JE, Nolley R, Hemenez M, Downs J. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol 2004;172:1297-1301. [CrossRef][ISI][Medline]
6. Crawford ED. PSA testing: what is the use? Lancet 2005;365:1447-1449. [CrossRef][ISI][Medline]
7. Dhir R, Vietmeier B, Arlotti J, et al. Early identification of individuals with prostate cancer in negative biopsies. J Urol 2004;171:1419-1423. [CrossRef][ISI][Medline]
8. Paul B, Dhir R, Landsittel D, Hitchens MR, Getzenberg RH. Detection of prostate cancer with a blood-based assay for early prostate cancer antigen. Cancer Res 2005;65:4097-4100. [Abstract/Full Text]
9. Ornstein DK, Rayford W, Fusaro VA, et al. Serum proteomic profiling can discriminate prostate cancer from benign prostates in men with total prostate specific antigen levels between 2.5 and 15.0 ng/ml. J Urol 2004;172:1302-1305. [CrossRef][ISI][Medline]
10. Tan EM. Autoantibodies as reporters identifying aberrant cellular mechanisms in tumorigenesis. J Clin Invest 2001;108:1411-1415. [Full Text]
11. Sahin U, Tureci O, Schmitt H, et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A 1995;92:11810-11813. [Abstract/Full Text]
12. Lee SY, Obata Y, Yoshida M, et al. Immunomic analysis of human sarcoma. Proc Natl Acad Sci U S A 2003;100:2651-2656. [Abstract/Full Text]
13. Wang X, Yu J, Sreekumar A, et al. Autoantibody signatures in prostate cancer. N Engl J Med 2005;353:1224-1235. [Abstract/Full Text]
14. Hakomori S. Glycosylation defining cancer malignancy: new wine in an old bottle. Proc Natl Acad Sci U S A 2002;99:10231-10233. [Full Text]
15. Mintz PJ, Kim J, Do KA, et al. Fingerprinting the circulating repertoire of antibodies from cancer patients. Nat Biotechnol 2003;21:57-63. [CrossRef][ISI][Medline]
16. Koziol JA, Zhang JY, Casiano CA, et al. Recursive partitioning as an approach to selection of immune markers for tumor diagnosis. Clin Cancer Res 2003;9:5120-5126. [Abstract/Full Text]
17. Kao H, Marto JA, Hoffmann TK, et al. Identification of cyclin B1 as a shared human epithelial tumor-associated antigen recognized by T cells. J Exp Med 2001;194:1313-1323. [Abstract/Full Text]
18. Suzuki H, Graziano DF, McKolanis J, Finn OJ. T cell-dependent antibody responses against aberrantly expressed cyclin B1 protein in patients with cancer and premalignant disease. Clin Cancer Res 2005;11:1521-1526. [Abstract/Full Text]
19. Li Y, Karjalainen A, Koskinen H, et al. p53 Autoantibodies predict subsequent development of cancer. Int J Cancer 2005;114:157-160. [CrossRef][ISI][Medline]
PDF
PDA Full Text
Add to Personal Archive
Add to Citation Manager
Notify a Friend
E-mail When Cited
Related Article
by Wang, X.Find Similar Articles |
