Association of HLA Class I Alterations with Tumor Escape and Cancer Progression

The identification of the genes encoding tumor-associated antigens (TAAs) and the development of means for immunizing against these antigens have opened new avenues for the development of an effective anti-cancer immunotherapy. However, current protocols of cancer immunotherapy aimed at enhancing anti-tumor T cell activity cause cancer regression only in a small number of patients (Rosenberg et al. 2004). Immune selection of CTL- and NK-cell-resistant tumor cells might explain the rapid progression and poor prognosis of cancers that exhibit HLA class I down-regulation. Thus, HLA class I downregulation represents a significant challenge for the successful application of cancer immunotherapy.

Recently, we have observed an interesting association of HLA class I expression and metastatic progression in a melanoma patient, whose subcutaneous metastases responded differently to autologous tumor cell vaccination (Cabrera et al. 2007). We analyzed three progressing and three regressing metastatic lesions for HLA class I expression using immunohistochemistry, tissue microdissection, LOH analysis, and other molecular techniques. Interestingly, the progressors had low HLA class I expression and higher frequency of LOH in chromosomes 6 and 15. In addition, all of the progressing metastases were HLA-B negative. Expression of class I molecules was normal in the regressing metastases. LOH at chromosome 6 was detected in all six studied metastases, suggesting that this defect may also be found in the primary tumor, contributing to the mechanism of tumor escape and metastatic progression. Real-time quantitative PCR of the samples obtained from microdissected tumor showed lower mRNA levels of HLA-ABC heavy chain and P2m in progressing metastases than in regressing ones, confirming the immunohistological findings. Sequence analysis of the P2m-coding region was performed in progressing metastasis, and no alterations of P2m region were found. The vaccination may have led to specific CTL immune responses against these tumor variants (with LOH in chromosome 6), leading to the expansion of new tumor variants with other alterations in HLA class I expression, including HLA locus B downregulation and LOH in chromosome 15. Reduced levels of HLA class I expression may be due to deletions in both HLA class I (LOH, chromosome 6) and P2m (LOH, chromosome 15) genes.

Similar correlations were previously described by our group in a murine model. MHC class I phenotype of metastatic lung colonies produced by a mouse fibrosar-coma tumor clone (B9) was MHC class I negative in immunocompetent mice and MHC class I positive in immunodeficient athymic nude/nude mice. In addition, TAP-1, TAP2, LMP2, LMP7, LMP10, tapasin, and calnexin mRNA were absent in metastases produced in immunocompetent mice. Interestingly, the MHC class I-positive or class I-negative phenotypes of the metastatic colonies correlated with in vivo immunogenicity (Garcia-Lora et al. 2003).

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