Human Leukocyte Antigen and Antigen Processing Machinery Component Defects in Astrocytic Tumors

Abstract

Purpose: To determine the frequency of abnormalities in human leukocyte antigen (HLA) and antigen processing machinery (APM) component expression in malignant brain tumors.This information may contribute to our understanding of the immune escape mechanisms used by malignant brain tumors because HLA antigens mediate interactions of tumor cells with the host's immune system. Experimental Design: Eighty-eight surgically removed malignant astrocytic tumors, classified according to the WHO criteria, were stained in immunoperoxidase reactions with monoclonal antibody recognizing monomorphic, locus-specific, and allospecific determinants of HLA class I antigens, h 2 -microglobulin, APM components (LMP2, LMP7, TAP1, TAP2, calnexin, calreticulin, and tapasin), and HLA class II antigens. Results: HLA class I antigens were lost in f50% of the 47 glioblastoma multiforme (GBM) lesions and in f20% of the 18 grade 2 astrocytoma lesions stained. Selective HLA-A2 antigen loss was observed in f80% of the 24 GBM lesions and in f50% of the 12 grade 2 astrocytoma lesions stained. HLA class I antigen loss was significantly (P < 0.025) correlated with tumor grade.Among the APM components investigated, tapasin expression was down-regulated in f20% of the GBM lesions analyzed; it was associated, although not significantly, with HLA class I antigen down-regulation and tumor grade. HLA class II antigen expression was detected in f30% of the 44 lesions analyzed. Conclusion: The presence of HLA antigen defects in malignant brain tumors may provide an explanation for the relatively poor clinical response rates observed in the majority of the T cellb ased immunotherapy clinical trials conducted to date in patients with malignant brain tumors.

HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells

“…The expression of MHC class-I molecules and therefore the immune recognition by CD8+ T cells are diminuished in gliomas as one mechanism of immune escape (Facoetti et al, 2005). In turn, reduced MHC class-I expression would lead to enhanced immune recognition by NK cells.…”

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

“…8,9 Loss of tapasin expression is a frequent event that has been reported in a wide variety of human cancers, including malignant melanoma, head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma, colorectal carcinoma, glioblastoma, lung carcinoma, and neuroblastoma. [10][11][12][13][14][15][16][17][18] Notably, tapasin expression associated with intratumoral T-cell infiltration has been reported as a prognostic marker of patient survival in ovarian carcinoma, HNSCC, glioblastoma, and colorectal carcinoma. 12,13,[19][20][21] It is also reported that loss of tapasin is more frequent among the other antigen-processing machinery (APM) components, strongly suggesting its central role in escape from CTL immune surveillance to tumors.…”

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

“…It is unlikely that other types of cells compensate for the lack of APC function of TIDC. Glioma cells work poorly as APC due to a low expression of MHC molecules and a lack of co-stimulatory molecules, which are needed to reactivate the primed T cells [37]. Microglia, which have been described to function as APC in vitro [38], are unable to present glioma cell antigens to cytotoxic T lymphocytes [39].…”