Biology Reference
In-Depth Information
with a total cost over $200 billion.
84
Although the
estimated
Although promising, these biomarkers await
validation in blinded, multicenter phase III
biomarker trials.
five-year overall survival after a cancer
diagnosis is 67%, there are few FDA-approved
biomarkers for early detection and monitoring
for disease recurrence, which could have signifi-
-
cant impact on clinical outcome. There is also
a need for biomarkers that identify biologic
subtypes of cancer and to predict responses to
a rising number of immune-targeted thera-
peutics, such as ipilimumab
85
and sipuleucel-T.
86
There is growing scienti
CHALLENGES AND FUTURE
DEVELOPMENT
Over the past decades, proteomic technolo-
gies have greatly contributed to the discovery
of novel autoantibody biomarkers. Emerging
methods enable the discovery of autoantigens
at the scale of proteomes. To this end, the
c evidence that
immune dysregulation functions the pathogen-
esis of cancer paradoxically, both contributing
to carcinogenesis through chronic in
eld
of proteomics has expanded our understanding
of the repertoire of antigens that can elicit auto-
antibodies in different diseases. Emerging data
from genomics and transcriptomics continues
to broaden the scope of potential immunogenic
structures to include mutated antigens and
splice variants that may have signi
amma-
tion
87
as well as controlling cancer progression
with direct immune surveillance of tumor anti-
gens.
88
e
90
Production of cytokines such as IL-6
and CSF-1 by tumor cells promotes the
development of immunosuppressive tumor-
associated macrophages (TAMs).
91,92
In model
systems, TAMs have been shown to directly
promote tumor progression and metastasis.
93
e
96
In contrast,
cant disease-
and tissue speci
city. In addition, proteomic
methods that can systematically display PTMs
are likely to identify numerous other autoanti-
body targets that are associated with disease.
The discovery and validation of these antigens
will improve our knowledge of the structural
content that elicits antibody immune responses,
and to understand the underlying mechanisms
of autoimmunity. These advances have potential
clinical implications for both biomarker develop-
ment and immune-targeted therapeutics.
ltrating lymphocytes
(TILs) are associated with improved survival
for lymphoma,
97
colorectal,
98,99
breast,
100
esoph-
ageal,
89
and ovarian cancers.
101
In particular, B
cell signatures
15,16
and intratumoral B cell folli-
cles
102
tumor-in
ed in multiple can-
cers
103
e
105
and are associated with improved
clinical outcome.
106
have been identi
These data suggest
that
cancers can induce an active, speci
c antibody
response to tumor-derived antigens.
There have been multiple proteomics-based
approaches to identify autoantibody biomarkers
that distinguish sera from cancer patients and
sera from healthy controls (
Table 4
). Speci
References
1. Ball J. Serum factor in rheumatoid arthritis aggluti-
nating sensitized sheep red cells. Lancet 1950;2(6637):
520
c
4.
2. Hargraves MM, Richmond H, Morton R. Presentation
of two bone marrow elements; the tart cell and the
L.E. cell. Proc Staff Meet Mayo Clin 1948;23(2):25
e
autoantibody signatures have been identi
ed
in the sera of patients from multiple cancer
types, often corresponding to overexpressed
tumor antigens. These autoantibodies are being
developed as potential biomarkers for early
cancer diagnosis, such as Annexin 1, 14-3-3
theta, and LAMR1 in lung cancer,
38
TA90 in
melanoma,
107
8.
3. Waaler E. On the occurrence of a factor in human
serum activating the speci
e
c agglutintion of sheep
blood corpuscles. Acta Path Micro Im A 2007;115(5):
422
38.
4. Lachmann PJ. A two-stage indirect L.E. cell
e
test.
and p53 in various cancers.
108
Immunology 1961;4:142
52.
e
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