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Calais da Silva et al. Systemic humoral responses during BCG treatment

agree with the idea that specific immunomodulatory experience relapse after BCG treatment and to help
molecules are involved in the success of BCG- design more personalized immune-based strategies.
treatment, but in moderate levels. Patients with For instance, a promising avenue of clinical research
relapsing tumors may be genetically prone to develop in bladder cancer is the use of immune checkpoint
exacerbated chronic inflammation or cytotoxic inhibitors that target molecules involved in the balance
responses during BCG treatment or during the and regulation of immune response, hence inducing
disease itself. This exacerbated inflammation may proper T-cell anti-cancer response. [30]
[24]
add to the burden of the disease. For instance, IFN-γ
is an essential component of cell-mediated immunity, In conclusion, the analysis of mRNA expression of
and in BCG therapy it has an inhibitory effect on PBMCs by real-time PCR was a relatively simple,
bladder cancer cells. However, depending on accurate technique for assessing the expression profile
[25]
signalling intensity and microenvironmental factors, of several key immunomodulators in patients with
this cytokine can drive novel cellular and molecular NMIBC, as compared with classical histopathological
inflammatory mechanisms that may underlie tumor evaluations and even with urine detection because not
initiation, immunoevasion, and progression. all patients have urine detectable levels.
[26]
Likewise, HMOX-1 catalyzes the degradation of heme
and is considered a key enzyme to protect cells from Our results revealed that molecules with
stress and to regulate cell growth and proliferation. immunomodulatory roles, such as IL-1β, IFN-γ,
However, increased levels of HMOX-1 expression HMOX-1, and GNLY, have a role in BCG therapy but
and activity were observed in various tumor tissues. only at certain amounts, above which they appear to
The knockdown of HMOX-1 suppresses the growth contribute to poor response to treatment. Thus, we
of bladder cancer cells, and HMOX-1 expression was established a cut-off value for mRNA levels of each
even proposed as an independent predictor of NMIBC molecule and propose the use of this information
recurrence and progression. This agrees with our to predict which patients with NMIBC will be good
[27]
data, showing that patients with lower levels of HMOX- BCG-responders, which patients will relapse when
1 before treatment are likely to respond better to undergoing BCG treatment, and who therefore would
BCG. On the other hand, granulysin is a cytolytic and benefit from alternative treatment strategies.
pro-inflammatory molecule expressed by activated
cytotoxic T cells and NK cells, necessary to kill Authors’ contributions
[28]
target cancer cells. However, it has been described Conceived and designed the study: H. Trindade, D.
that granulysin kills bacteria and therefore it may Ligeiro, F.M. Calais da Silva, F.E. Calais da Silva
[29]
lessen the efficacy of BCG therapy. Performed literature search and prepared manuscript:
P.A. Videira, M.G. Cabral
Our results point to the fact that the systemic expression Acquired clinical data: F.M. Calais da Silva, F.E. Calais
of molecules that promote inflammation is involved da Silva
in BCG host response. However, since inflammatory Performed the experimental study and data acquisition:
response shares various molecular targets and D. Ligeiro
signaling pathways with the carcinogenic process, a Analyzed data and prepared presentation of
good BCG response occurs only within limited levels manuscript: P.A. Videira
of these molecules. Taking this into consideration, we Performed statistical analysis: R. Sylvester
define cut-off values for mRNA levels of IL-1β, IFN-γ, Revised the manuscript: F.M. Calais da Silva, P.A.
HMOX-1, and GNLY, beneath which a good response Videira, D. Ligeiro, M.G. Cabral, R. Sylvester, F.E.
to BCG is predicted. This allowed us to discriminate Calais da Silva, H. Trindade
BCG responders from relapsing patients.
Acknowledgments
Univariate and multivariate analysis showed that IL- We thank João Sobral, Helena Gouveia, and Sofia
1β, IFN-γ, HMOX-1, and GNLY expression levels Mendes for help in preparing patients’ samples
could reliably predict responder vs. relapsing patients. and data.
Based on our data, we established cut-off values
above which these biomarkers are considered a Financial support and sponsorship
prejudicial factor. We subdivided patients into whether This work was supported by a grant of Astellas Pharma,
they showed no prejudicial factors, one prejudicial obtained after application.
factor, or two prejudicial factors (see supplementary
data). We also established a predictive grouping Conflicts of interest
system to identify the probability that patients would There are no conflicts of interest.
124 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 14, 2017