Expression of HLA class I/II antigens and T cell immune response in human neuroendocrine tumors of the pancreas

Abstract

Peptide presentation by HLA class I and II antigens regulates specific antigen recognition by T cells. The present study aimed to investigate T cell infiltration and its relation to HLA antigen expression in pancreatic neuroendocrine tumors. Fresh tissue samples were collected from five insulinomas and six other neuroendocrine tumors (one gastrinoma, one glucagonoma, two carcinoid, and two neuroendocrine carcinomas). Normal pancreatic and splenic tissue samples were used as controls. Investigation of infiltrating lymphocyte populations, as well as staining of HLA class I and II antigens, were performed by standard immunohistochemistry. The majority of investigated tumors demonstrated an intratumoral infiltration by CD3+, CD4+ and CD8+ T cells that was significantly higher than in normal pancreatic islets. Only a minority of tumor-infiltrating T cells showed the CD45RO+ phenotype. The expression of HLA class I antigen was altered in 10 of 11 tumors. A loss of beta-2microglobulin represented the most frequent type of alteration to HLA class I expression, although the total loss of HLA class I was found in only one case of neuroendocrine carcinoma. HLA class II molecules were expressed by endothelial and lymphoid cells and not by tumor cells. In conclusion most neuroendocrine pancreatic tumors induce a T cell mediated immune response resulting in an intratumoral infiltration with CD3+, CD4+ and CD8+ T cells. Loss of beta-2microglobulin is a frequent alteration in these tumors, which may influence the normal function of the HLA class I antigen complex. In contrast to malignant tumors of the exocrine pancreas, expression of HLA class II was absent in neuendocrine pancreatic tumor cells.

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

“…Tumour-associated antigens (TAAs), along with cytokines from NET cells, dendritic cells (DCs) and tumour-associated macrophages, recruit/induce regulatory T cells (Tregs), which inhibit the anti-tumour immune response (Ameri & Ferone 2012). Altered expression of HLA class I molecules has been demonstrated in ten out of 11 pancreatic NETs, loss of b2-microglobulin being the most frequent alteration (Ryschich et al 2003). Immunohistochemical analysis of four patients with lung NET revealed the complete absence of cells expressing DC markers CD1a and CD83, and induction of apoptosis in DCs is a key mechanism by which tumours escape immune recognition and elimination (Katsenelson et al 2001).…”

Diffuse Endocrine System, Neuroendocrine Tumors and Immunity: What’s New?

“…That an immune response opposes to NETs is also substantiated by the frequent finding of lymphocyte infiltration of NETs, as assessed by immunohistochemistry for CD3 (a general T lymphocyte marker), CD4, and CD8 [61,62,63]. In the biggest case series analyzed so far, CD3+ T cells were found to infiltrate 68% of 87 well-differentiated pancreatic NETs.…”

“…An altered expression of HLA class I molecules has been demonstrated by immunohistochemistry in 10 out of 11 pancreatic NETs, loss of β2-microglobulin being the most frequent alteration [61]. In the absence of HLA class I antigens, TAA-derived peptides cannot be presented to T cells and the development of a tumor-specific immune response is hindered.…”

“…After polyclonal activation, patients’ T cells proliferated less than those from controls, possibly because of an anergized state caused by carcinoid-associated Treg [62]. NET-infiltrating Treg have been detected by immunohistochemistry for single Treg markers [62,63], even though such an approach is not optimal to identify Treg and no Treg within NETs have been reported too [61]. Treg infiltration tended to be heavier in metastases than in primary carcinoid tumors [62].…”

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“…were the first to demonstrate the presence of CD3+ T cells in pancreatic neuroendocrine tumors (PNET) [18]. Later, a series published by Kat et al from Memorial Sloan Kettering analyzed post-operative tumor specimens of 87 patients with primary PNET for TILs.…”