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Molecular Oncology, Markers, Clinical Correlates |
Departments of 1 Pathology, 2 Medicine, 3 Surgery, 4 Radiotherapy and Radiology, and 5 Equipe Cytokines et Cancers - INSERM U590 Lyon, France; 6 Unité d’Oncologie Médicale, Hôpital Edouard Herriot, Lyon, France; and 7 Laboratory for Immunological Research Schering-Plough Research Institute, Dardilly, France
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Experimental Design: T lymphocytes and DC infiltration within primary tumors was investigated in 152 patients with invasive nonmetastatic breast cancer. CD1a, CD3, CD68, CD123, CD207/Langerin, and CD208/DC-LAMP expression was assessed with semiquantitative immunohistochemical analysis. Expression of chemokines involved in DC migration (MIP-3a/CCL20, MIP-3b/CCL19, and 6Ckine/CCL21) was also examined. The correlation between these markers and the characteristics of the tumors, as well as relapse-free and overall survival was analyzed. Significant prognostic parameters were then tested in a validation series.
Results: Infiltration by immature CD207/Langerin+ DC was found in a third of the cancers and did not correlate with clinicopathological data. Presence of mature CD208/DC-LAMP+ DC (56%) and CD3+ T cells (82%) strongly correlated with lymph node involvement and tumor grade. Among the chemokines analyzed, only the presence of MIP-3b/CCL19 in 57% of the tumors correlated with prolonged overall survival. CD123+ plasmacytoid DC (pDC) infiltrated 13% of the primary tumors. Their presence was strongly associated with shorter overall survival (93% versus 58% at 60 months) and relapse-free survival (90% versus 37% at 60 months) and was found to be an independent prognostic factor for overall survival and relapse-free survival and confirmed in an independent validation series of 103 patients.
Conclusions: Infiltration by pDC of primary localized breast tumor correlates with an adverse outcome, suggesting their contribution in the progression of breast cancer.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Several lines of evidence suggest that the immune response may also influence the progression of tumors. The concept of tumor immunosurveillance, which was proposed more than 40 years ago (6) , has been supported in humans by epidemiologic studies revealing a correlation between clinical immunosuppression and cancer development (7) . Tumor immunosurveillance was recently shown through the use of tumor-prone and immunodeficient mice (8 , 9) . The capacity of both innate resistance and adaptative immunity to affect the progression of tumors has been shown in several mouse models (10 , 11) and, more recently, in patients receiving tumor-specific vaccine (12) . However, the role of the T-cell–mediated immune response in controlling cancer progression remains poorly documented.
In primary breast cancer, an efficient antitumor immune response has not been shown, although dendritic cells (DC) infiltrate the tumors (13) and antibodies directed against p53 (14) or HER-2/neu (15) have been detected in the sera of patients. Indeed, unlike other tumor types, the incidence of breast cancer is not altered in immunocompromised patients (16) , and some nonspecific immunostimulating therapies have been suggested to worsen the prognosis (17) . Immature DC have been recently shown to infiltrate primary breast carcinoma, whereas mature DC were only found at the periphery of the tumor (13 , 18) . However, the clinical relevance of this observation remains unclear because immature DC infiltration in primary breast carcinoma does not correlate with improved survival (19 , 20) in contrast to other tumor types (21, 22, 23) .
The present study confirms that the frequent infiltration of primary breast carcinomas by myeloid DC does not correlate with prognosis. However, a strong correlation was observed between plasmacytoid DC (pDC) infiltration and poor survival, suggesting a contribution of these immune cells in tumor progression.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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. The median follow-up of the series is 60 months (range 2 to 72).
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and show that, although similar, the tumor size was on average smaller with a lower frequency of lymph node invasion than in the 1996 series. The median follow-up of the series is 58 months (range 6 to 68 months).
Treatment.
All of the patients were treated according to the following procedures: radical mastectomy for central tumors or tumors larger than 3 cm, conservative surgery followed by radiotherapy for the remaining patients. Adjuvant chemotherapy with anthracyclins was given to node-positive patients and to node-negative patients with two or more of the following criteria: tumor larger than 3 cm, Scarff-Bloom-Richardson grading index (SBR; a pathological index of tumor aggressiveness) of grade 2 to 3, and negative estrogen receptor, and progesterone receptor expression. Adjuvant chemotherapy with anthracyclins was given to T4d tumors. Tamoxifen 20 mg/day was given for 5 years in patients with estrogen receptor or progesterone receptor expressing tumors.
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Immunohistochemical Staining |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Semiquantitative Evaluation of the Stainings |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Statistical Analysis |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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2 test or Fisher exact test in Table 2
. The correlation between the different phenotypic markers of immune cells was also tested with the Pearson test. Survival curves were plotted with the Kaplan Meier method, and we used the log-rank test to compare survival. Multivariate analysis of prognostic factors for overall survival and relapse-free survival was done with the Cox model. All statistical analysis was done with the procedures of the SPSS 10.02 package.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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describes the presence and phenotype of immune cells, as well as the chemokine and chemokine receptor expression pattern in the 1996 series of 152 patients with primary invasive nonmetastatic breast tumors. Examples of immunohistochemical stainings obtained for markers with clinical relevance are presented in Fig. 1
. One hundred and twelve tumors from this series were infiltrated by DC. Present in almost one-third of the tumors, CD207/Langerin+ and CD1a+ DC displayed tight contacts with cancer cells (Fig. 1A
; data not shown). CD207/Langerin and CD1a expressions were highly correlated (r = 0.71, P < 0.0001). Fifty-six percent of the tumors contained CD208/DC-LAMP+ mature DC (Fig. 1B)
, which were consistently located within CD3+ T-cell infiltrates. Indeed, a strong correlation was observed between CD208/DC-LAMP expression and CD3+ T-lymphocyte infiltrates (Fig. 1A
; r = 0.73, P < 0.0001). Thirteen percent of the tumors were infiltrated by CD123+ small racquet-shaped cells with an eccentric nucleus that correspond to the typical morphology of pDC (Fig. 1C
; ref. 24
). Using BDCA2 staining on paraffin sections, these CD123+ cells were also found to express BDCA2, a marker specific for pDC (ref. 25
; Fig. 1D
). Identification of pDC was additionally confirmed by double CD123/BDCA2 staining of frozen sections originating from the same tumors (data not shown). Of note, CD123+ pDC were never found within CD3+ T-cell infiltrates, but sometimes occurred in the vicinity of tumor cells (Fig. 1, C and D)
. Interestingly, an anti-MxA monoclonal antibody did not stain pDC in any of the 20 tumors of the 1996 series infiltrated with pDC, suggesting that those cells were not secreting type I IFN (data not shown; ref. 26
). CCL20 was not detectable in this series (data not shown). CCL19 and CCL21 expression was observed both in tumor cells and DC (Table 1
; data not shown). Of note, CCL21 expression was also observed occasionally in lymphatic endothelial cells (data not shown).
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Survival and Immune Cell Infiltration.
As expected, both overall survival and relapse-free survival were significantly reduced in patients with large tumors, nodal involvement, and high SBR grade (Table 3)
. In addition, in univariate analysis, the presence of CD123+ cells was identified as an adverse prognostic factor for both overall survival and relapse-free survival, whereas the presence of CCL19 was significantly associated with an improved overall survival but not relapse-free survival (Fig. 2
; Table 3
). In contrast, no significant correlation was found between expression of CD1a, CD207/Langerin, CD3, CD208/DC-LAMP, hCCL21, or CD68 and either overall survival or relapse-free survival (data not shown).
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. The presence of CCL19 was an independent, positive prognostic factor for overall survival only (Fig. 2
; Table 4
). Survival curves illustrate the striking differences of both relapse-free and overall survival between patients with or without pDC infiltration of their tumors (Fig. 2)
.
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).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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DC are professional antigen-presenting cells that play a sentinel role in both peripheral organs and in peripheral blood. On triggering by microbial products or by tissue damage, they migrate to secondary lymphoid organs where they present antigen to T cells (27) . Antigen presentation leads to T-cell proliferation, which results in either immunity or tolerance depending on the stage of maturation of the presenting DC (28) . The nature of the T-cell response is also dependent on the subpopulation of DC involved. Indeed, two major human DC populations have been recognized, the myeloid DC and the pDC. They differ in many aspects, including their origin, their migratory ability and tissue localization, their capacity to discriminate and to respond to different pathogens, and the profile of cytokines they secrete (29) . In response to various stimuli, myeloid DC and pDC can polarize the type of T-cell response toward a Th1 or a Th2 response, depending primarily on interleukin-12 secretion (30) . The two DC subtypes also contribute in different ways to link acquired and innate immune responses, with myeloid DC-activating B cells (31) and NK cells (32) , and pDC producing large amounts of natural IFNs in response to viruses (33) .
Given the functional differences defined by both the activation status and the subpopulations under consideration, we have revisited the role of DC in the biology of early breast cancer. For this purpose, tumors were retrieved from files of patients who had their primary breast cancer resected at the regional Cancer Center (Centre Léon Bérard). This prospective and exhaustive series included the first 152 patients with primary invasive nonmetastatic breast carcinomas that were diagnosed in 1996. The tumor characteristics were comparable with those from other series of patients in large comprehensive cancer centers in terms of tumor size, nodal involvement, HER2/neu+++ overexpression, and SBR grading. HER2/neu+++ was also found to correlate with high SBR grading and low hormone receptor expression (data not shown), as well as with a poor relapse-free survival. Several parameters were selected for investigation: CD1a and CD207/Langerin, two markers of Langerhans-type immature DC; CD123, a marker of pDC; and CD208/DC-LAMP, a molecule expressed specifically by mature DC (34) . Immunostaining was also done to evaluate the expression of hCCL20, hCCL19, and hCCL21, which are known to drive immature and mature DC migration, respectively (35) . In addition, CD3+ lymphocyte and CD68+ macrophage infiltrates were studied.
Langerhans-type DC were detected in about one-third of primary breast tumors, in contrast with our previous report, where all of the frozen tissue sections were infiltrated by CD1a+ and/or CD207/Langerin+ DC (13) . This discrepancy might be because of differences in patient populations or may reflect a lower sensitivity of immunostaining on paraffin-embedded tissue sections. It has been reported by several groups that the density of CD1a+ DC in various types of cancer is associated with an improved prognosis (21, 22, 23 , 36 , 37) . However, in agreement with previous reports in primary breast adenocarcinomas (19 , 20) , no correlation with overall survival or relapse-free survival was observed in the present series.
Over half of primary breast tumors analyzed were infiltrated by mature (CD208/DC-LAMP+) DC. The striking compartmentalization of immature tumor-infiltrating DC within tumor bed and mature tumor-infiltrating DC within peritumoral clusters of T cells was confirmed in this study (13 , 18) . A strong association between the presence of CD208/DC-LAMP+ and CD3+ cells was observed, but the density of both mature DC and T-cell infiltrates did not correlate with the prognosis. Whether the CD208/DC-LAMP+ tumor-infiltrating DC are of myeloid or plasmacytoid origin remains to be formally determined, but the nonoverlapping localization of CD208/DC-LAMP+ and CD123+/BDCA-2+ cells on serial tissue sections (data not shown) suggests they are of myeloid origin. The direct correlation with axillary lymph node metastasis, SBR, HER2/neu, and inverse correlation with hormone receptor status suggest the association of CD3 and CD208/DC-LAMP infiltrate with more aggressive tumors. In particular, immune infiltrate could either reflect HER2/neu immunogenicity or indicate a pathogenic role of immune cells that may contribute to HER2/neu+ tumor progression. However, neither CD3 nor CD208/DC-LAMP was significantly associated with overall survival or relapse-free survival in univariate analysis in the whole series.
CCL21 and CCL19, two ligands for CCR7, were expressed (by tumors cells, stromal cells, or both) in 7% and 57% of the samples, respectively. Although the expression of these two chemokines did not correlate with tumor size, nodal status, SBR grade, or hormone receptor status, CCL19 expression was associated in both univariate and multivariate analyses with a favorable overall survival (98% rate at 5 years) but not with relapse-free survival. The mechanism underlying this observation is unclear: CCL19 may attract mature DC and T lymphocytes that could contribute to control tumor progression (38, 39, 40, 41) . However, no correlation was observed between tumor-infiltrating DC or CD3+ T-cell infiltrates and either CCL19 expression or prognosis (data not shown).
The main observation of this study is the adverse prognostic value of CD123+ pDC infiltration in the tumor for overall survival and relapse-free survival. The presence of pDC in breast metastatic lymph node (42) , in malignant ascites (43) , and in primary melanoma (44) has previously been reported, but no attempt has been made thus far to correlate the pDC infiltration with clinical data. Patients with pDC infiltrates in the primary tumor had a 58% and 73% overall survival at 5 years in the test and the validation series, respectively, and only a 37% relapse-free survival in both series. In marked contrast, patients without pDC infiltrate had a favorable evolution: subgroups of patients with T1–2, T3–4, and N+ tumors all had an overall survival >90% at 5 years in this series with a long follow-up.
Different nonexclusive mechanisms may account for the association between tumor pDC infiltration and poor prognosis. Infiltration by pDC may merely mark a subset of aggressive primary breast cancers with an intrinsic propensity to metastasize. Alternatively, tumor-infiltrating pDC may enhance tumor growth by the production of angiogenic factors (17 , 45) , proteases and/or motility factors that can modify the microenvironment of breast cancer (46) . Finally, tumor-infiltrating pDC may facilitate tumor progression by interfering with the immune response as follows: (a) tumor-infiltrating pDC may induce T-cell tolerance either directly (47) or through the generation of tumor-specific, interleukin-10–secreting CD4+ (47) and/or CD8+ T-suppressor cells (48) ; (b) tumor-infiltrating pDC may deviate the tumor-specific T-cell response toward a Th2 phenotype (30) , which seems less effective against tumors; and (c) through natural IFN secretion, tumor-infiltrating pDC may alter the presentation of tumor-associated antigens to T cells by myeloid DC. Indeed, pDC may inhibit the differentiation of monocytes into DC, reduce the antigen-presentation capacity of myeloid DC (49) , or even convert myeloid DC into mediators of immune tolerance. This last hypothesis is unlikely, however, given the absence of MxA in tumor-infiltrating pDC, which suggests that they are not actively secreting type I IFN in situ (26) . Nevertheless, the understanding of the mechanisms by which pDC contribute to tumor progression could reveal a new therapeutic target. The key role of CXCL12 in recruiting pDC that express CXCR4 in malignant ovarian ascites was established recently (43) . However, such a function for CXCR4 ligand seems to be less evident in breast tumors, as no correlation could be found between the presence of this chemokine and the infiltration of pDC (data not shown). Whether blood vessels of some breast tumors overexpress adhesion molecules such as PNAd that may help pDC precursors to extravasate (50) remains to be determined.
In conclusion, this first description of a strong correlation between pDC infiltration in breast tumor and poor prognosis may provide a novel prognostic marker for primary breast cancer that could assist in deciding how to optimize the use of current therapies. A larger multicentric study is being set up to confirm these data. Furthermore, by suggesting a role for the immune system in the control of primary breast adenocarcinoma, these findings open new perspectives for the treatment of cancer patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: I. Treilleux, J-Y. Blay, and N. Bendriss-Vermare contributed equally to this work.
Requests for reprints: Jean-Yves Blay, Equipe Cytokines et Cancers, INSERM U590, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon cedex 08, France. Phone: 33-4-78-78-27-50; Fax: 33-4-78-78-27-20; E-mail: blay{at}lyon.fnclcc.fr
Received 4/ 9/04; revised 6/28/04; accepted 8/17/04.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSImmunohistochemical StainingSemiquantitative Evaluation of...Statistical AnalysisRESULTSDISCUSSIONREFERENCES |
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