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

INTRODUCTION cytotoxic cells], and cytotoxic T lymphocyte antigen-4
(CTLA4) expressed by activated/exhausted T cell; and
Non-muscle-invasive bladder cancer (NMIBC) has an (5) molecules involved in stress homeostatic events
increasing incidence and a high relapse rate, even such as heme oxygenase 1 (HMOX-1). The tight
after transurethral resection of the bladder tumor balance of such mediators is critical for the efficacy
(TURBT), the initial standard treatment. Due to the of BCG immunotherapy. Despite this knowledge, the
frequent need for follow-up procedures, NMIBC precise immune mechanism involved in BCG therapy
significantly reduces quality of life and is one of the is still not completely clarified. Assessing immune
most expensive malignancies to treat. Post-TURBT response is thus fundamental to an understanding of
intravesical instillation of Bacille Calmette-Guérin BCG-induced antitumor mechanism and its prognostic
(BCG), the attenuate strain of Mycobacterium bovis, is value.
the recommended treatment for intermediate and high-
risk NMIBC, by preventing relapse and progression Interestingly, in many bacterial infections, analysis
[1]
of NMIBC -- stages Ta, T1 and carcinoma in situ. While of immunomodulators detected in peripheral blood
partially successful, 30% to 50% of the patients do not cells is extremely relevant to following a patient’s
[12]
respond and experience relapse within the first year of immune response. Blood is the predominant sample
BCG treatment. Of these patients, 15% develop tumor substrate for systemic analysis, and it allows depiction
progression and form distant metastases. [2] of the overall inflammation burden that accompanies
infection.
Despite many efforts, [3-5] there are currently no
biomarkers that can predict patient’s prognosis and Significant changes in the number and function of
that discriminate those who will respond to BCG peripheral blood cells have been reported over the
treatment from those who would be best served course of BCG therapy, such as the increase in
by more aggressive therapy such as cystectomy BCG-activated killer (BAK) cells. Few attempts
[8]
or, alternatively, radio- and chemotherapy. BCG have been made to assess the relevance of the
instillations can cause side effects ranging from systemic cytokine profile in peripheral blood cells. [13,14]
incommodious cystitis to sepsis and even death of However, the expression of cytokines and other BCG-
patients in rare cases. This fact reinforces the need induced mediators that are systemically detected
for selecting and accompanying patients who enroll in over the course of BCG instillation has never been
BCG immunotherapy. properly addressed. In this work, we sought to profile
the expression of key molecules expressed by blood
Treatment with BCG was first used empirically by cells of NMIBC patients during BCG treatment. We
Morales in 1976. Today, it is well assumed that the analyzed the expression of cytokines TNF-α; IL-
[6]
efficacy of BCG is based on a massive, complex, 10; IFN-γ, IL-1β, IL-2, IL-4 and IL-6; chemokines
and ongoing local immune activation. Hence, a CCL2, CCL3, CCL8, CXCL9 and IP-10; mediators
healthy host immune system is a prerequisite to of cytotoxic response CTLA4, Fas-L, Perf, GNLY
successful BCG therapy. [1,7,8] Within bladder tissue, and NOS2A; and HMOX-1, which is involved in
the leukocyte distribution before and after BCG homeostatic events. We established predictive cut-off
therapy is remarkably different, and the induction of values and developed a predictive grouping system
complex inflammatory cascade events, reflecting that allows us to identify the most likely patients to
activation of multiple types of immune cells, is relapse after BCG treatment.
well known. [9,10] The cascade of events results in
secretion of an array of cytokines, chemokines, and METHODS
cytotoxicity mediators that can be detected in tissue
and in urine. [7,11] These are summarized in Table 1. Patients
Examples are (1) pro-inflammatory, T helper type 1 From July 2005 until July 2007, 58 patients [mean age
(Th1) cytokines such as interleukin (IL)-1β, IL-2, IL- of 67.8 years (range 45 to 82)] were assisted at the
6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ; Hospital São José, Lisbon, Portugal and diagnosed
(2) Th2 cytokines IL-4 and IL-10; (3) chemokines, as with NMIBC. Patients were BCG naïve and with
CCL2, CCL8, CCL3, IFN-γ-inducible protein (IP-10), high-risk tumors (T1 tumor, G3** [HG] tumor), CIS,
CXCL9; (4) cytotoxicity mediators, such as nitric oxide multiple and recurrent and large (> 3 cm) Ta, G1G2
(NO) released by macrophages, and mediators of tumors, and they were treated with the same dose
cytotoxic response such as perforin (Perf), granulysin of BCG instillations (TICE BCG) after TURBT. They
®
(GNLY), and Fas ligand (Fas-L) pathway released entered this study after informed consent. BCG
by cytolytic lymphocytes [natural killer (NK) and T instillations were repeated once a week for 6 weeks
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 14, 2017 117