Provided that this difference is not caused by the distinct characteristics of the two mAbs used to measure the expression level of the gene products of HLA-A and of HLA-B and C loci, it may reflect the different characteristics of the tumor antigens presented by HLA-A antigens and by HLA-B and C antigens including but not limited to their range of specificity and to their immunogenicity. An additional difference between our study and that of Rodig em et al /em 12 is that in the latter study biopsy samples obtained from metastases in several distinct anatomic sites were included. I antigen expression level in lymph node metastases, but not in cutaneous or subcutaneous metastases was significantly correlated to density of CD8+ and CD45RO+ T cells and of lymphocytes expressing PD-1, as well as to clinical response and to patients survival. Conclusions Our results corroborate the role of HLA class I expression level (alone or in combination with T-cell density values) as a predictive biomarker of response to ipilimumab in patients with melanoma. In addition, our results show that this association is influenced by the anatomic site of the metastasis used to measure the HLA class I antigen expression level. strong class=”kwd-title” Keywords: HLA, immunology, oncology, tumors Introduction Immunotherapy with monoclonal antibodies (mAbs) targeting immune checkpoints has been shown to induce durable clinical responses in an increasing number of cancer types. However, only a percentage (between about 10% and 40% depending on tumor type when used as monotherapy) of the treated patients benefits from this therapy.1 Rabbit polyclonal to ANTXR1 Its efficacy will be greatly increased by the identification of biomarkers able to predict clinical response to therapy and by the development of strategies to counteract resistance mechanisms to immune checkpoint inhibitors (ICIs).2 3 The Helioxanthin 8-1 available evidence strongly suggests that ICI-based therapy is effective in patients bearing tumors with high mutational burden (therefore containing a large number of potential neoantigens), and showing high immunological activity (immune cell infiltration, immune response-related gene expression).1 3 4 Helioxanthin 8-1 Effective antitumor immune response is Helioxanthin 8-1 dependent on the recognition of tumor antigens by antigen-specific T lymphocytes in the context of human leukocyte antigen (HLA) class I molecules. To this end, expression of a fully functional HLA class I antigen processing machinery (APM) by tumor cells is crucial for the recognition and destruction of tumor cells by cognate cluster of differentiation (CD)8+ T cells. Defects in HLA class I APM component expression have been reported to be associated with disease progression and poor prognosis in several cancer types.5 6 Moreover, functional HLA class I APM is expected to be crucial for the success of T-cell-based immunotherapies. Mutation or loss of heterozygosity of 2-microglobulin (2M), an essential component of the HLA class I complex, was identified as a mechanism Helioxanthin 8-1 of primary and acquired resistance to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors7C9 as well as other types of T-cell-based immunotherapies.10 However, structural mutations leading to defective HLA class I APM component expression and/or function have a frequency of less than 10%.6 Defects of HLA class I APM component expression are most frequently caused by epigenetic mechanisms.6 11 Nevertheless, the association of HLA class I protein expression with response to ICI therapy1 has been investigated only to a limited extent,12 and only two studies have addressed the association between HLA class II antigen expression on tumor cells and response to ICI.12 13 In a recent study we examined infiltration of 11 immune cell types in pretreatment surgical samples of patients with metastatic melanoma treated with ipilimumab. We found a positive association between immune cell density in lymph Helioxanthin 8-1 node metastases and response to ICI therapy for several cell types, including CD4+ and CD8+ T lymphocytes, forkhead box P3 (FOXP3+) cells, CD20+ B lymphocytes, NKp46+ NK (natural killer) cells, and cells expressing the activation markers CD134 or CD137.14 The aim of the present study was to analyze HLA class I and class II expression in the set of samples we had previously analyzed for immune cell infiltration, to correlate it with T-cell infiltration and to assess its value as a biomarker of clinical response to ipilimumab therapy and survival in patients with metastatic melanoma. Materials and methods Tumor samples Archived paraffin blocks of pretreatment surgical tissue samples (50 lymph node and 35 cutaneous/subcutaneous metastases) were collected from 30 patients with metastatic melanoma who received ipilimumab treatment between 2010 and 2014. The clinical characteristics of this patient cohort, previously.