IgG IMMUNE RESPONSE TO TUMOR

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Exp Oncol 2005
27, 2, 136-140
Experimental Oncology 27, 136-140, 2005 (June)
IgG IMMUNE RESPONSE TO TUMOR-ASSOCIATED CARBOHYDRATE
ANTIGENS (TF, Tn, aGal) IN PATIENTS WITH BREAST CANCER:
IMPACT OF NEOADJUVANT CHEMOTHERAPY AND RELATION
TO THE SURVIVAL
O. Kurtenkov1,*, K. Klaamas1, K. Rittenhouse-Olson2,3,
L. Vahter4, B. Sergejev1, L. Miljukhina1, L. Shljapnikova1
1
National Institute for Health Development, Tallinn 11619, Estonia
2
Department of Biotechnical and Clinical Laboratory Sciences,
The University at Buffalo, Buffalo, NY 14214, USA
3
Department of Microbiology and Immunology, The University at Buffalo, Buffalo, NY 14214, USA
4
Estonian Cancer Centre, Tallinn 11619, Estonia
Aim: Tostudy the humoral immune response to tumor-associated carbohydrate epitopes (TF, Tn and aGal) in patients
with breast cancer and healthy donors, the putative impact of the chemotherapy and to evaluate if the level of
antibody to these epitopes might be beneficial or detrimental for the patients with breast cancer. Materials and
methods: The humoral immune response to TF, Tn and aGal was studied in 133 patients with breast cancer, including
the patients at stage II–III (n = 44) before and after neoadjuvant chemotherapy (10 patients received cyclophosphamide/methotrexate/fluorouracyl (CMF) chemotherapy regimens, 34 patients received cyclophosphamide/doxorubicin/fluorouracil (CAF)), and in controls (healthy donors and patients with fibroadenoma). Fully synthetic carbohydrate hapten-polyacrylamide conjugates were used as antigens in ELISA for anti-carbohydrate antibody determination. The correlation analysis between the level of anti-carbohydrate antibodies and the stage of cancer, histological
grade, expression of TF and aGal epitopes in tumor tissue, patient’s survival was performed. Results: The level of
anti-carbohydrate antibodies varied between individuals with no significant correlation between IgG immune response to the three epitopes. Lower levels of antibodies were observed at advanced stages of cancer. Neoadjuvant
chemotherapy stimulated antibody production to Tn and aGal epitopes (increase > 50%) in about one third of
patients. Immunosuppression, decrease in antibody levels, was observed only in 4.5–13.6% of cases. High levels of
TF-antigen specific IgG antibody before surgery were associated with a better survival time of stage II breast cancer
patients. Conclusion: The widely used regimens of neoadjuvant chemotherapy (such as CMF, CAF) can stimulate the
immune response to tumor-associated carbohydrate epitopes in some patients. The high levels of anti-TF antibody
before surgery are associated with a better survival of stage II breast cancer patients. This may indicate that the
selection of immunopotentiating regimens of neoadjuvant chemotherapy might be beneficial for the host.
Key Words: breast cancer, tumor-associated carbohydrate antigens, natural antibodies, cancer chemotherapy,
immunomodulation, survival.
In women, breast cancer is the most common malignancy in many parts of the world, with an increase in morbidity of about 33% in 10 years [3]. Its incidence and mortality ranks the first place in women of Estonia. The course
of the disease as well as the efficacy of chemotherapy
and the survival rate in patients who have undergone surgery is difficult to predict at the individual level. This suggests that breast carcinomas are very heterogeneous in
their biological and clinical behaviour and there are many
tumor- and/or host-related factors that influence the natural course of the disease and its clinical outcome.
The occurrence of altered glycosylation of tumorassociated glycoconjugates has been well established
[6, 8, 11]. Short and less branched oligosaccharides
are characteristic for malignant cells. Tumor-associated blood group-related carbohydrate antigens have
been reported to be related to the biological behaviour
Received: May 19, 2005.
Correspondence:
Fax: 372 6593901
E-mail: oleg.kurtenkov@tai.ee
Abbreviations used: CAF — cyclophosphamide/doxorubicin/fluorouracil; CMF — cyclophosphamide/methotrexate/fluorouracil.
of cancer and to the prognosis of cancer patients or
experimental animals [1, 12, 19, 25].
At least three tumor-associated carbohydrate epitopes
[Tn (GalNAca1-O-Ser/Thr), Thomsen-Friedenreich (TF)
(Galb1-3GalNAca/b-O-Ser/Thr), and the a-galactosyl
(aGal) epitope (Gala1-3Galb1-4GlcNAc-R)] differ from
other epitopes in that they are immunogenic in the host.
Every individual has an appreciable amount of natural antibodies to these epitopes [9, 24]. These antibodies are
considered by some to be one of the mechanisms of natural resistance against cancer [2, 4, 24]. Therefore, it is
possible that modulation of the immune response to these
epitopes during the chemotherapy might be beneficial or
detrimental for the patient.
In the present study, the IgG immune response to TF,
Tn and aGal epitope in patients with breast cancer was
measured before and after neoadjuvant chemotherapy. We
found that widely used regimens of neoadjuvant chemotherapy (such as CMF, CAF) can stimulate the immune
response to these antigens in some patients and that high
levels of anti-TF antibody before surgery is associated with
a better survival of stage II breast cancer patients.
Experimental Oncology 27, 136-140, 2005 (June)
MATERIAL AND METHODS
Patients and healthy donors. The patients with histologically verified breast carcinoma (n = 133) were included in the study. The patients were classified by stage
of the disease according to the international pTNMG
system. The patients with fibroadenoma of the breast
(n = 50) and blood transfusion donors (29 women) were
included as controls. The number and median age of
subjects tested and the distribution by the stage of disease is presented in Table 1. The patients at stage II–III
(n = 44) were tested before and after 3 courses of neoadjuvant chemotherapy. Two widely used standard chemotherapy regimens were applied: cyclophosphamide/
methotrexate/fluorouracyl (CMF, 10 patients) and CAF
(doxorubicin instead of methothrexate, 34 patients). All
patients and controls were above 40 years old. Serum
was stored at –20 °C until tested.
Determination of serum IgG antibodies to TF, Tn
and aGal glycotopes by enzyme-linked immunosorbent assay (ELISA). Sera were tested as described
elsewere [14, 16]. Briefly: the plates were coated with
synthetic oligosaccharide-polyacrylamide (PAA) conjugates (Synthesom, Munich, Germany; 10 mol % of carbohydrate for TF disaccharide and 20 mol % for other
epitopes) in carbonate buffer, pH 9.6, and incubated at
4 °C overnight. After washing with PBS-0.05% Tween
20 and blocking with 1% bovine serum albumin (BSA),
patients’serum (diluted 1 : 50 in PBS-Tween, 5 mM
EDTA) was added and incubated for 2 h at room temperature (26 °C). After additional washing with PBSTween the bound IgG was detected with alkaline phosphatase-conjugated rabbit anti-human IgG (Dako, Denmark) and p-nitrophenylphosphate (Sigma, St.Louis,
MO). The reaction was quantitated at 405 nm in ELISA
reader (Labsystem Multiscan MCC/340, Finland). Patients were divided into “weak” and “strong” responders:
the (O.D.) values equal or less than median O.D. for the
whole cancer group were considered as “weak responders” and those with O.D. values more than the median
O.D. were considered as “strong” responders.
Expression of TF and aGal epitope in tumor tissue. The expression of TF epitope in tumor was estimated semiquantitatively by immunohistochemistry on
formalin-fixed paraffin-embedded tissue sections (14 patients). After deparaffinization and blocking with 1% BSA,
the sections were incubated with T antigen specific Mab
JAA-F11 [21] (20 mg of MAb per ml) for 1.5 h at room
temperature). After washing, the secondary antibody,
rabbit biotin-labelled anti-mouse immunoglobulin (Dako,
Denmark) was added (1 : 200) and incubated with the
tissue for 30 min at room temperature. The streptavidinalkaline conjugate (DakoCytomation, Denmark) diluted
1 : 200 and NBT-BCIP (Sigma) were used for immunostaining. Intensity of staining was scored as (+/-) negative or equivocal; (+) moderate; (++) intense. Semiquantitative analysis of aGal epitope expression was
performed using biotinylated aGal specific Bandeiraea
simplicifolia lectin (4 mg/ml); streptavidin-alkaline conjugate (DakoCytomation, Denmark) diluted 1 : 200 and
NBT-BCIP (Sigma) were applied. A section in which the
137
lectin or Mab was replaced by PBS was always added
as a negative control.
Statistical methods. All calculations and comparisons were made using SPSS software, version 10.0.5.
Antibody levels (O.D. values) were analysed by MannWhitney test and Pearson’s correlation. Fisher’s exact
test was used for small groups to evaluate the association between pathohistological parameters (T, G
grade) and the expression of epitopes in tumor tissue.
The cumulative survival of cancer patients was estimated by the Kaplan-Meier method. The log-rank test
was used to compare differencies in survival between
the groups; the “strong” and “weak” responders were
compared within each stage of the disease. The differences were considered significant if P < 0.05.
RESULTS
The levels of IgG antibodies (O.D. values) to TF, Tn
and aGal epitope before treatment are presented in Fig 1.
Compared to blood donors, lower levels of anti-TF
and anti-Tn antibody were noted in patients with advanced cancer. In contrast, significantly lower levels of
Fig. 1. IgG antibody level (O.D.values ± SD) to TF, Tn and aGal
antigens in healthy donors, patients with breast cancer and fibroadenoma. P values are shown for the significant differences
in IgG antibody levels between patients and healthy donors as
calculated by Mann-Whitney test.
* P < 0.05; ** P < 0.002.
138
Experimental Oncology 27, 136-140, 2005 (June)
anti-aGal antibodies were observed already at the early
stages of cancer. Slightly higher levels of anti-Tn antibodies were noted for a group of women with fibroadenoma compared to both blood donors and patients with
breast cancer. In addition to the stage-related changes, an association with the pathohistological findings
was found for anti-TF antibody level. It was lower in
patients with undifferentiated tumors (G3) compared
to those with G1 group (0.28 ± 0.13 and 0.42 ± 0.12,
respectively; n = 63, P < 0.05). A progressive decrease
of TF antigen specific IgG antibody levels were observed depending on tumor size with a significant difference between T1 and T4 groups: 0.4 ± 0.36 and
0.25 ± 0.08, respectively (P < 0.02).
The levels of antibodies to various carbohydrate
epitopes did not correlate with each other. The only correlation observed was between anti-TF and anti-Tn antibody level in cancer patients with stage I (r = 0.317, Ð =
0.05) and stage II (r = 0.536, Ð < 0.001). A slight positive
correlation was also noted between anti-TF and antiaGal antibodies in patients at stage I (r = 0.42, Ð = 0.05).
Expression of TF and aGal epitope in tumor tissue. MAb JAA-F11 positive immunohistochemical cellmembrane or cytoplasmic staining was found in 10 of
14 tumor samples tested. In four samples, the staining
was classified semiquantitatively as weak (+), in 2 —
moderate (2+), and in 4 patients — strong (3+). The
last group showed a trend to a higher level of anti-TF
IgG antibody (P = 0.12, Fisher’s exact test). Only in
4 tumor samples of 14, weak expression of aGal specific BSI-4 lectin-positive material was detected. No association between the expression of TF or aGal epitope
in the tumor and the antibody levels to any of the antigens tested was observed.
Impact of neoadjuvant chemotherapy. Three
types of the changes in the antibody levels were seen
after neoadjuvant chemotherapy: an increase of the
antibody level (> 50%), no appreciable changes (± 50%)
and a suppression of the response (Table 2).
The level of TF antigen specific antibodies remained
rather stable with chemotherapy. In contrast, 31.8% of
patients showed an increase of anti-Tn and -aGal IgG
antibody levels after 3 courses of chemotherapy. There
was no significant difference in the response to CAF or
CMF therapy except that a higher proportion (60%) of
patients with an increase in anti-Tn IgG response received
CMF, rather than to CAF therapy (23.5%, P = 0.039). An
increase of anti-Tn and anti-aGal IgG was mostly noted
in patients who had initially low level of antibody before
treatment. It’s necessary to note that only 4–13% of the
patients showed the decrease in antibody levels.
Relation to the survival. The cumulative survival
of patients was analysed in relation to the level of anticarbohydrate antibodies before surgery. The stage II
patients with high levels of TF antigen specific antibodies showed better cumulative survival time: the
mean ± SD values for stage IIb patients were 38.0 ±
8.9 and 43.0 ± 2.5 months, P = 0.06 (log-rank test) for
“weak” and “strong” responders, respectively (Fig. 2, b).
A similar trend was observed for the patients at stage IIa:
39.0 ± 1.49 and 43.0 ± 2.3 months, P = 0.07 (Fig. 2, a).
In contrast, high levels of anti-Tn antibody in this group
were associated with worse survival (P = 0.16). Patients at stage III did not show any association. No relationship to survival was found for anti-Tn and antiaGal antibody levels. Patients with stage III disease had
low levels of anti-TF (P = 0.03).
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Fig. 2. Cumulative survival plots (Kaplan-Meier) of stage IIa and
IIb breast cancer patients depending on the level of anti-TF IgG
antibody in their serum.
Dark line — patients with high level of antibody (“strong responders”); dotted line — “weak responders” with low level of TF antibody. a — stage IIa (n = 24); b — stage IIb (n = 13). P values as
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DISCUSSION
The data showed that the level of anti-carbohydrate
antibodies varied considerably between individuals. Intestinal resident microflora, expression of these glycotopes on old erythrocytes or crypt antigens, which are
present on normal glycoconjugates may be considered
as potential antigenic stimuli [10, 23]. However, compared to blood donors, a majority of patients with can-
Experimental Oncology 27, 136-140, 2005 (June)
cer showed significantly lower levels of antibody to aGal
and TF glycotopes, especially in later stages of the disease. Some increase in anti-TF IgG antibody level was
observed in patients at stage I. The level of anti-Tn antibodies was rather stable and less dependent on the
disease stage. No significant correlation between the
antibodies specific to various glycotopes was observed.
We have previously shown our anti-carbohydrate antibody assays to be highly specific [22]. It’s necessary to
note, that stage-related changes in anti-TF antigen
specific IgG antibody level in patients with various types
of cancer were less pronounced than the IgM TF antibodies that has been found to show dramatic changes,
uniformly falling by the early stages of cancer [7, 16,
24]. Low level of these antibodies was also shown to
be associated with premalignant conditions and with a
higher risk for cancer development [14, 24, 25].
Antibody production to Tn and aGal epitopes was
stimulated after neoadjuvant chemotherapy in about
one third of patients, mostly in those with low level of
antibodies before treatment. Immunosuppression was
observed only in 4.5-13.6% of cases, thus suggesting
that immune response to carbohydrate epitopes studied was rather resistant to neoadjuvant chemotherapy. The anti-Tn and anti-aGal antibody levels as detected before surgery were not related to the remote
prognosis. In contrast, high level of TF-antigen specific
IgG antibodies before surgery was associated with a
better survival time of stage II breast cancer patients
and it may be of value as a prognostic indicator.
We recently found highly significant (P < 0.00001)
associations of better survival of radically operated patients with early stages of gastric cancer with higher
levels of TF antigen-specific IgG antibodies [15]. It appears that there is the same trend for stage II breast
cancer patients. This suggests that high level of TF specific antibodies at the moment of tumor removal may
be beneficial for the patient. No association between T
antibody level and survival was noted for patients with
advanced gastric cancer (unpublished data) and
stage III breast cancer. It seems that this mechanism
may be effective for elimination of only small number of
tumor cells or micrometastasis which appear in the circulation after surgery, thus preventing or delaying relapse and improving the survival. It is possible that there
is a restorative effect of surgical removal of primary tumor on cell-mediated and humoral immunity [5], but
the effect of the antibody blockade on metastatic adhesion processes should also be considered. The finding that expression of TF and aGal epitopes in tumor is
not related to the level of IgG antibody to these epitopes
indicates that no strong acquired IgG immune response
is induced by autologous tumors. Despite the observation that only small proportion of patients demonstrated an increase in TF antigen specific antibody level after chemotherapy it cannot be excluded that other
regimens or other chemotherapeutic agents might have
such an immunopotentiated effect. It has been reported that the levels and repertoire of natural antibody to
ubiquitous autoimmunogenic epitopes are rather sta-
139
ble over time and seems to be strongly genetically determined [13]. This suggests that the level of naturally
occuring antibody may be important in the destruction
of circulating tumor cells after surgery. The efficacy of
cancer immunotherapy with mucin-type vaccines [17,
19, 25] further supports that tumor-related simple carbohydrate epitopes may be promising targets for such
therapy especially when multi-epitope vaccines are
used [18, 20]. Thus, neoadjuvant chemotherapy may
be in part considered as immunotherapy in terms of its
immunomodulating effect on immune response to tumor-related carbohydrate epitopes.
Based on our results, at least two aspects may be
of interest for further study and clinical value: (i) the
selection of chemotherapeutic regimens with anti-tumor immuno-enhancing potential or the avoidance of
immunosuppressive chemotherapeutic agents (such
effects may be tested before surgery during the neoadjuvant chemotherapy) and (ii) the use of preoperative level of T antigen specific antibodies as a prognostic predictor.
ACKNOWLEDGMENTS
This study was supported by grants ¹ 3635 and
¹ 5436 from the Estonian Science Foundation.
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ÈÌÌÓÍÍÛÉ ÎÒÂÅÒ ÍÀ ÎÏÓÕÎËÜÀÑÑÎÖÈÈÐÎÂÀÍÍÛÅ
ÓÃËÅÂÎÄÍÛÅ ÀÍÒÈÃÅÍÛ (TF, Tn, aGal) Ó ÁÎËÜÍÛÕ ÐÀÊÎÌ
ÌÎËÎ×ÍÎÉ ÆÅËÅÇÛ: ÂËÈßÍÈÅ ÍÅÎÀÄÚÞÂÀÍÒÍÎÉ
ÕÈÌÈÎÒÅÐÀÏÈÈ È ÑÂßÇÜ Ñ ÂÛÆÈÂÀÅÌÎÑÒÜÞ ÁÎËÜÍÛÕ
Öåëü: èññëåäîâàòü ãóìîðàëüíûé èììóííûé îòâåò íà îïóõîëüàññîöèèðîâàííûå óãëåâîäíûå àíòèãåíû (TF, Tn and
aGal) ó áîëüíûõ ðàêîì ìîëî÷íîé æåëåçû, îöåíèòü âîçìîæíîå âëèÿíèå õèìèîòåðàïèè íà ýòîò îòâåò è ñâÿçü ñ
âûæèâàåìîñòüþ áîëüíûõ. Ïàöèåíòû è ìåòîäû: ãóìîðàëüíûé èììóííûé îòâåò íà TF, Tn, aGal áûë èçó÷åí ó 133
áîëüíûõ ðàêîì ìîëî÷íîé æåëåçû, â òîì ÷èñëå ó áîëüíûõ ñî ñòàäèÿìè II–III, ïîëó÷àâøèìè íåîàäúþâàíòíóþ õèìèîòåðàïèþ (n = 44), è â êîíòðîëüíûõ ãðóïïàõ (äîíîðû êðîâè è áîëüíûå ñ ôèáðîàäåíîìîé ìîëî÷íîé æåëåçû). Äëÿ
îïðåäåëåíèÿ óðîâíÿ àíòèòåë ñèíòåòè÷åñêèå ïîëèàêðèëàìèä-ãàïòåí êîíúþãàòû áûëè èñïîëüçîâàíû â êà÷åñòâå àíòèãåíîâ â èììóíîôåðìåíòíîì àíàëèçå. Ïðîàíàëèçèðîâàíà êîððåëÿöèÿ ìåæäó óðîâíåì àíòèòåë ê ðàçëè÷íûì ýïèòîïàì è
ñòàäèåé ðàêà, äàííûìè ãèñòîëîãèè, ýêñïðåññèåé TF è aGal ýïèòîïîâ â îïóõîëåâîé òêàíè è ñ âûæèâàåìîñòüþ áîëüíûõ.
Ðåçóëüòàòû: óðîâíè àíòèòåë ê ðàçíûì ýïèòîïàì âàðüèðîâàëè ìåæäó ïàöèåíòàìè è íå êîððåëèðîâàëè ìåæäó ñîáîé.
Áîëåå íèçêèå óðîâíè àíòèòåë îòìå÷åíû ó áîëüíûõ íà ïîçäíèõ ñòàäèÿõ ðàêà. Íåîàäúþâàíòíàÿ õèìèîòåðàïèÿ ñòèìóëèðîâàëà (áîëåå ÷åì íà 50%) ïðîäóêöèþ Tn è aGal ñïåöèôè÷åñêèõ àíòèòåë ïðèìåðíî ó îäíîé òðåòè áîëüíûõ. Ñíèæåíèå
óðîâíÿ àíòèòåë îòìå÷åíî ëèøü â 4.5–13.6% ñëó÷àåâ. Îáíàðóæåíà êîððåëÿöèÿ ìåæäó âûñîêèì óðîâíåì àíòè-TF IgG
àíòèòåë äî îïåðàöèè è óëó÷øåíèåì âûæèâàåìîñòè áîëüíûõ ñî II ñòàäèåé îïóõîëåâîãî ïðîöåññà. Âûâîäû: øèðîêî
ïðèìåíÿåìûå ðåæèìû íåîàäüþâàíòíîé õèìèîòåðàïèè (òàêèå, êàê CMF, CAF) ìîãóò îêàçûâàòü ïîòåíöèðóþùèé ýôôåêò íà èììóííûé îòâåò ê îïóõîëüàññîöèèðîâàííûì óãëåâîäíûì ýïèòîïàì ó íåêîòîðûõ áîëüíûõ. Âûñîêèé óðîâåíü
àíòè-TF àíòèòåë êîððåëèðóåò ñ ëó÷øåé âûæèâàåìîñòüþ áîëüíûõ ðàêîì ìîëî÷íîé æåëåçû II ñòàäèè. Ïðåäïîëàãàåòñÿ, ÷òî ñåëåêöèÿ èììóíîïîòåíöèðóþùèõ ðåæèìîâ õèìèîòåðàïèè ìîæåò áûòü ïîëåçíîé äëÿ ïàöèåíòà.
Êëþ÷åâûå ñëîâà: ðàê ìîëî÷íîé æåëåçû, îïóõîëüàññîöèèðîâàííûå àíòèãåíû, åñòåñòâåííûå àíòèòåëà, õèìèîòåðàïèÿ ðàêà, èììóíîìîäóëÿöèÿ, âûæèâàåìîñòü.
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