Abstract
BackgroundTumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens. TIL are also increasingly recognised as possible prognostic parameters. However, the effects observed are variable indicating that results cannot be extrapolated from type of tumour to another. Moreover, it has been suggested that primary solid tumours may be ignored by the immune system and that a meaningful immune response is only mounted in regional lymph nodes.MethodsWe have examined the local distribution of immune cells in tumour-related compartments in head and neck squamous cell carcinomas (HNSCC). In a second step, the prognostic impact of these cells on disease-free survival (DFS) was analysed. A total of 198 tissue cores from 33 patients were evaluated using tissue mircroarray technique and immunohistochemistry. Tumour-infiltrating immune cells were identified using antibodies specific for CD3, CD8, GranzymeB, FoxP3, CD20 and CD68 and quantified using an image analysis system.ResultsWe demonstrate a relative expansion of FoxP3+ regulatory T-cells (Treg) and of cytotoxic T-cells among tumour infitrating T-cells. We also show that intratumoural CD20+ B-cells are significantly more frequent in metastatic deposits than in primary tumours. Furthermore, we observed a reduced number of peritumoural CD8+ T-cells in metastatic lymph nodes as compared to univolved regional nodes suggesting a local down-modulation of cellular immunity. All other immune cells did not show significant alterations in distribution. We did not observe an association of tumour infiltrating immune cells at the primary site with outcome. However, increased numbers of intraepithelial CD8+ TIL in metastatic tumours as well as large numbers of peritumoural B-cells in lymph node metastases were associated with favourable outcome. Unexpectedly, no effect on patient outcome was observed for Treg in any compartment.ConclusionOur results suggest that alterations in lymphocyte distribution in regional lymph nodes rather than at the primary tumour site may be relevant for patient prognosis. Moreover, we demonstrate that in addition to cellular immunity humoral immune responses may be clinically relevant in anti-tumour immunity.
Highlights
Tumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens
Our results suggest that alterations in lymphocyte distribution in regional lymph nodes rather than at the primary tumour site may be relevant for patient prognosis
Mean CD20+ cell infiltration was significantly increased in metastatic lymph node deposits compared to primary tumour (p < 0.005) and CD8+ lymphocytes were significantly more frequent in uninvolved draining nodes compared to peritumoural lymphatic tissue of metastatic lymph nodes (p < 0.022)
Summary
Tumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens. CD8+ cytotoxic T-cells (CTL) are considered to be the major effector immune cells directed against tumour cells This notion is supported by the observation that cytotoxic TIL are an indicator of favourable prognosis in certain carcinomas while tumour-infiltrating regulatory T-cells (Treg) have been shown to be associated with unfavourable prognosis in ovarian cancer [3,4,5,6]. In early stage breast cancer, sentinel and axillary lymph nodes displayed reduced numbers of CD4+ and CD8+ T-cells as compared to control lymph nodes while highest numbers of CD1a+ dendritic cells were seen in uninvolved axillary nodes [11] Some of these effects, notably a reduction in the numbers of CD4+ T-cells were observed in draining axillary nodes even in the absence of metastatic deposits suggesting that alterations of immune profiles in regional lymph nodes may occur independently of tumour invasion [11]. Large numbers of CD4+-lymphocytes and of CD1a+dendritic cells predicted more precisely for NED-survival than axillary lymph node metastasis per se indicating an important functional role of an immune cell distribution shift [11]
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