Guardian and Selective Killer: The Versatile Functions of TLR3 in Hepatocellular Carcinoma
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Guardian and s elective Killer: the Versatile Functions of tlr3 in Hepatocellular Carcinoma
Chen Liu 0 1 2
0 Affiliations of authors: Department of Pharmacy, University of Washington , Seattle, WA (JJC , SDR); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center , Seattle, WA, SDR , USA
1 Gainesville , FL 32610 , USA
2 Affiliation of author: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida , Gainesville, FL, CL , USA
to populations. First, molecular testing is as much about generating cost savings by identifying nonresponders as it is about improving survival by identifying responders. In this context, highly accurate tests are needed to mitigate the potential negative survival impacts of misclassification. Second, molecular tests are probably not as good as they might first seem. Community practice is messy. Tests will be inconsistently applied and evaluated. Patients discontinue therapies more quickly than they do in registration studies. Distant metastases are much more difficult to manage than they are in clinical trials. A?good model will account for these issues because decision makers recognize they are part of the real world and want to know how they influence the results, even if those results become less favorable. Even accounting for these issues, KRAS testing for mCRC proves to be a bit of a no brainer; the test has sufficiently favorable sensitivity, specificity, and cost so that the clinical and economic rationale for its use is highly apparent. So what was the value of building a complex decision model for this problem? First, as we noted, it highlights the fact that real-world considerations attenuate the value of modern molecular tests, even those with high levels of analytical validity and clinical utility. Second, the authors have shown that the BRAF test, although it may have poorer performance characteristics than the KRAS test, can still save health resources without substantially sacrificing outcomes. Finally, and most importantly, this study of an unusually accurate test raises important issues that should be considered for other molecular tests in other settings. The ?sacrifice? in life expectancy in the testing vs no-testing comparison is trivial because there are very few false-negative tests and because the targeted therapies are relatively safe and offer modest survival Notes The authors report no conflicts of interest.
Current chemotherapy and radiation therapies for hepatocellular
carcinoma (HCC), which causes 500,000 deaths per year
worldwide, are not very effective. The recently approved multikinase
inhibitor Sorafenib modestly improves survival by a few months
in some patients with advanced cancer (
). Surgical resection and
liver transplantation can be performed in less than 20% of patients.
Thus, development of novel diagnostic and prognostic approaches
and therapeutic modalities for HCC is urgently needed. HCC is
unique compared with other human cancers because the majority
of HCC occurs in patients with chronic liver diseases, especially
viral hepatitis (ie, hepatitis B and hepatitis C) and liver cirrhosis due
to various etiologies (
). The latent period from the original disease
to the development of HCC usually ranges from 10 to 30? years;
this long window of time provides an opportunity for investigating
cancer development and designing strategies for intervention.
To achieve this end, a better understanding of the mechanisms
by which HCC develops and progresses is critically important.
The common denominator underlying HCC carcinogenesis is
inflammation, a form of host immune defense. It is most obvious
in the setting of viral hepatitis, especially hepatitis C viral
infection. Hepatitis C virus is the major etiological factor for HCC in
most developed countries. Hepatitis C virus has an ability to evade
its host?s innate and adaptive immune system and establish
persistent infection, resulting in lasting inflammatory response in the
). Although the detailed molecular cascades are not entirely
known, there is no doubt that inflammation can cause genetic and
epigenetic dysregulation in hepatocytes and, eventually, cell
transformation. Once cancer is established in the liver, the host?s innate
and adaptive immune system still persistently attempts to eradicate
or slow the cancer cell growth. Recent studies have demonstrated
that the vigor and breadth of the immune system play a critical
role in the outcome of HCC (
). However, the mechanism of
how various components of the immune system interact with HCC
remains a mystery.
The innate immune response against cancer is important because
it not only directly attacks cancer cells but also primes specific and
long-lasting adaptive immune response. In HCC patients,
antigenspecific T cells are detectable, which indicates that both innate
and adaptive immune responses are operative in HCC. Despite
this immune response, cancer still prevails. One explanation for
the insufficient immune surveillance is that immunosuppressive
function mediated by regulatory T cells and myeloid-derived
suppressor cells is upregulated in HCC patients (
). The increased
infiltration of these immunosuppressive cells creates an
immunosuppressive milieu in tumor tissue, which is associated with a bleak
clinical prognosis. Studies showed that modulation of regulatory
T cells improved overall antitumor immunity (
). Whether this
strategy can be successfully used in HCC immunotherapy remains
to be investigated. In addition, there are many other immune cells
that infiltrate HCC cancer tissue, such as natural killer (NK) cells,
macrophages, and different subsets of T and B cells. These cells
can produce numerous cytokines that are almost certain to affect
the tumor microenvironment. Moreover, HCC cells are capable
of making molecules that counter the host immune response (10).
Understanding the tumor microenvironment will undoubtedly
help us figure out how to shift a tumor-friendly environment to a
When discussing inflammatory reactions, a well-known
proinflammatory family of proteins cannot be ignored. Initially
considered key receptors to sense pathogens and activate the innate
immune response against bacterial, viral, and fungal infection,
Toll-like receptors (TLRs) have been recently recognized to play a
role in cancer (
). Expression of different members of TLRs has
been reported in a number of human cancers (
). However the
functional role of TLRs is much more complicated. Both protumor
growth and antitumor activities were reported (
). Clearly more
experiments are needed to unravel the biological role of TLRs in
cancer. More important, we need to find out how to use the
knowledge for cancer therapy because multiple TLR agonists have been
In this issue of the Journal, Chew et?al. present their intriguing
study on the role and the underlying mechanism of TLR3 in HCC
). This study brings attention to the effect of innate immunity
on HCC progression and its clinical outcome. The investigators
examined the expression levels of TLR3 in 172 human liver cancer
tissues from predominantly female (82%) patients and found that
increased TLR3 expression is positively correlated with a longer
survival for HCC patients. Using immunohistochemical staining,
they identified TLR3 overexpression in both HCC cancer cells
and tumor-infiltrating NK cells and, independently, that higher
expression of TLR3 on either cell population is associated with longer
survival. The investigators then performed a series of experiments to
demonstrate that activation of TLR3 by polyinosinic:polycytidylic
acid (poly I:C) caused apoptosis of the TLR3-positive HCC cell lines,
whereas similarly activated TLR3 promoted NK cell proliferation
and increased NK cell antitumor activity. The investigators further
examined the impact of TLR3 activation on cancer cells and immune
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on 26 May 2018
cells in mouse models. Similar to the in vitro observation, they
found that both T cells and NK cells proliferated upon poly (I:C)
treatment, whereas in vivo the HCC cells exhibited fourfold lower
proliferation and an 11-fold increase in tumor cell apoptosis. The
findings suggest that effects of TLR3 are quite different in immune
cells and in cancer cells. The tantalizing questions are how TLR3
knows how to act differently in normal and cancer cells and what the
downstream signaling molecules?are.
Chew et? al. also examined the effect of TLR3 activation in
murine HCC models (
). When mice with endogenous HCC
were treated with poly (I:C), there was increased expression of Ccl5
and CXCL9 in both the HCC cancer cells and tumor-infiltrating
leukocytes. NK cell numbers also increased; these cells appeared
to be activated in the tumors. The authors further demonstrated
in a transplant HCC mouse model that the expression of Ccl5 and
CXCL9 increased tumor-infiltrating lymphocytes and suppressed
the tumor growth. The data seem to suggest that TLR3 may
function through induction of these two cytokines. This interpretation
may be an oversimplification of a much more sophisticated process.
It is well known that TLR3 can activate interferon regulatory
factor 3 (IRF3) and induce abundant production of type 1 interferons.
One has to wonder what happens to interferons in the tumor and
what role interferons play. It is a relevant question because
interferons have an antitumor effect on many types of human cancers,
including HCC, as well as an immune regulatory effect.
One of the most interesting findings from this study is the
demonstration of the multiple functions of TLR3: slowing
cancer cell proliferation, increasing apoptosis, and attracting NK cells
and T cells and enhancing their proliferation and antitumor effect.
These functions are all beneficial for fighting cancer, at least in
HCC. It is not surprising that TLR3 can cause HCC apoptosis
because it has been shown before that TLR3 and IRF3 activation
induces the production of tumor necrosis factor?related
apoptosis-inducing ligand (
). The puzzle is why this TLR3-mediated
pathway does not act earlier to stop the cancer in the first place.
Because hepatitis C virus has an ability to interfere with TLR3
), it is possible that cancer cells can act similarly.
Although the molecular mechanisms remain to be defined,
activation of TLR3 appears to be beneficial for HCC patients and
raises the hope that TLR3 can be used as a target for
immunotherapy. The use of TLR3 agonists in this study provides proof
of concept. However, the immune system can be a double-edged
sword, and we must proceed carefully with experimental therapy.
The challenge is how to kill cancer cells without causing damage to
noncancerous hepatocytes. The nontumor liver tissue has its own
unique microenvironment created by interaction between viruses
and immune responses, and we should focus on how to selectively
turn on TLR3 in cancer tissues but not in the whole liver or the
whole body. The timing, intensity, and location of certain immune
functions are paramount to maintain homeostasis while fighting
off disease. Understanding how TLRs or other innate immune
components operate in the cancer microenvironment will certainly
enhance our ability to fine-tune the immune system to fight cancer.
JNCI | Editorials 1781
The author has no conflicts of interest to disclose. The sponsors had no role in
the writing of the editorial or the decision to submit the editorial for publication.
an aspirin a day: the allure (and distraction) of
Isra G. Levy, Carolyn P. Pim
Controlling cancer by using one or more chemical compounds to
prevent its occurrence has held tantalizing promise for decades (
Nearly 30? years ago, when the research community was exploring
the potential of ascorbic acid and ?-tocopherol, proponents observed
that chemoprevention had a solid theoretical base and examples of
protection from neoplasia in experimental animals had been
). Subsequently, chemoprevention trials have shown mixed
results. Studies have disappointed for the effects of ?-carotene,
?-tocopherol, retinol, retinyl palmitate, N-acetylcysteine, and
isotretinoin on lung cancer (
), one of the more intensely studied
organ systems. On the other hand, use of selective estrogen
receptor modulators, such as tamoxifen, has been shown to reduce the
incidence of breast cancer in high-risk women (
), and dutasteride
has been shown to decrease the incidence of prostate cancer (
Funding for chemoprevention studies through the National Cancer
Institute?s Research Portfolio has been robust for many years, with
more than $200 million nominally allocated to this topic in 2011 (
Aspirin (acetylsalicylic acid) has been promoted as a
chemoprevention agent for cardiovascular disease for more than 60?years (
1782 Editorials | JNCI
Evidence has now accumulated that daily aspirin reduces the
longterm risk of death due to cancer too (
). However, although
aspirin has been shown to reduce incidence of colorectal cancer, the
effects on incidence of other cancers are essentially unknown (9).
Meanwhile, other nonsteroidal anti-inflammatory drugs (NSAIDs)
have also shown promise in cancer chemoprevention. COX2
inhibitors, which slow the cyclooxygenase enzymes involved in the
synthesis of prostaglandins, appear to prevent colon and breast cancer
). In this issue of the Journal, Sahasrabuddhe et?al. (
the preventive benefits of NSAIDs for primary hepatocellular
cancer (HCC) and the presumed intermediate surrogate of chronic
inflammatory liver disease. The investigators make the promising
observation that, in a large, prospective, cohort study, use of aspirin
and other NSAIDs was associated with lower risk of death due to
chronic inflammatory liver disease, and aspirin use was linked to
reduced risk of developing HCC. Although the emerging research
findings on cancer impacts have not yet translated into clinical
recommendations such as those for prevention of vascular disease by
the use of daily aspirin, the hype is building. A? Google search of
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