Although malignant cells can be recognized and controlled by the immune system, in patients with clinically apparent cancer immunosurveillance has failed. To better understand local immunoregulatory processes that impact on cancer progression, we correlated intratumoral immunological profiles with the survival of patients affected by primary clear cell renal cell carcinoma (ccRCC). A retrospective analysis of 54 primary ccRCC samples for 31 different immune response-related transcripts, revealed a negative correlation of CD68 (a marker of tumor-associated macrophages, TAMs) and FOXP3 (a marker of regulatory T cells, Tregs) with survival. The subsequent analysis of 12 TAM-related transcripts revealed an association between the genes coding for CD163, interferon regulatory factor 4 (IRF4) and fibronectin 1 (FN1), all of which have been linked to the M2 TAM phenotype, with reduced survival and increased tumor stage, whereas the opposite was the case for the M1-associated gene coding for inducible nitric oxide synthetase (iNOS). The M2 signature of (CD68+) TAMs was found to correlate with CD163 expression, as determined in prospectively collected fresh ccRCC tissue samples. Upon co-culture with autologous tumor cells, CD11b+ cells isolated from paired blood samples expressed CD163 and other M2-associated proteins, suggesting that the malignant cells promote the accumulation of M2 TAMs. Furthermore, the tumor-associated milieu as well as isolated TAMs induced the skewing of autologous, blood-derived CD4+ T cells toward a more immunosuppressive phenotype, as shown by decreased production of effector cytokines, increased production of interleukin-10 (IL-10) and enhanced expression of the co-inhibitory molecules programmed death 1 (PD-1) and T-cell immunoglobulin mucin 3 (TIM-3). Taken together, our data suggest that ccRCC progressively attracts macrophages and induces their skewing into M2 TAMs, in turn subverting tumor-infiltrating T cells such that immunoregulatory functions are increased at the expense of effector functions.

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Renal cell carcinoma (RCC) is a heterogeneous group of kidney cancers with clear cell RCC (ccRCC) as the major subgroup. To expand the number of clinically relevant tumor-associated antigens (TAA) that can be targeted by immunotherapy, we analyzed samples from 23 patients with primary ccRCC for the expression and immunogenicity of various TAAs. We found high-frequency expression of MAGE-A9 and NY-ESO-1 in 36% and 55% of samples, respectively, and overexpression of PRAME, RAGE-1, CA-IX, Cyclin D1, ADFP, C-MET, and RGS-5 in many of the tumor samples. We analyzed the blood of patients with HLA-A2 þ ccRCC for the presence of CD8 þ T cells specific for TAA-derived HLA-A2-restricted peptides and found spontaneous responses to cyclin D1 in 5 of 6 patients with Cyclin D1-positive tumors. Cyclin D1-specific CD8 þ T cells secreted TNF-a, IFN-g, and interleukin-2 (IL-2), and degranulated, indicating the presence of polyfunctional tumor-specific CD8 þ T cells in the blood of these patients with ccRCC. The high frequency (43%) of Cyclin D1 overexpression and the presence of functional cyclin D1-specific T cells in 83% of these patients with ccRCC suggest that cyclin D1 may be a target for immunotherapeutic strategies. Cancer Immunol Res; 1(5); 288-95. Ó2013 AACR.

JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival. Leukemia 2010; 24: 105-109.

<p>PDF file - 444K, Supplementary Figure S1: Cyclin D1-specific tetramer staining in PBMCs and TILs of ccRCC patients. Supplementary Figure S2: Imunoblotting for Cyclin D1 in sera of ccRCC patients.</p>

<div>Abstract<p>Renal cell carcinoma (RCC) is a heterogeneous group of kidney cancers with clear cell RCC (ccRCC) as the major subgroup. To expand the number of clinically relevant tumor-associated antigens (TAA) that can be targeted by immunotherapy, we analyzed samples from 23 patients with primary ccRCC for the expression and immunogenicity of various TAAs. We found high-frequency expression of <i>MAGE-A9</i> and <i>NY-ESO-1</i> in 36% and 55% of samples, respectively, and overexpression of <i>PRAME</i>, <i>RAGE-1</i>, <i>CA-IX</i>, <i>Cyclin D1</i>, <i>ADFP</i>, <i>C-MET</i>, and <i>RGS-5</i> in many of the tumor samples. We analyzed the blood of patients with HLA-A2⁺ ccRCC for the presence of CD8⁺ T cells specific for TAA-derived HLA-A2–restricted peptides and found spontaneous responses to cyclin D1 in 5 of 6 patients with <i>Cyclin D1</i>–positive tumors. Cyclin D1–specific CD8⁺ T cells secreted TNF-α, IFN-γ, and interleukin-2 (IL-2), and degranulated, indicating the presence of polyfunctional tumor-specific CD8⁺ T cells in the blood of these patients with ccRCC. The high frequency (43%) of <i>Cyclin D1</i> overexpression and the presence of functional cyclin D1–specific T cells in 83% of these patients with ccRCC suggest that cyclin D1 may be a target for immunotherapeutic strategies. <i>Cancer Immunol Res; 1(5); 288–95. ©2013 AACR</i>.</p></div>

<p>PDF file - 444K, Supplementary Figure S1: Cyclin D1-specific tetramer staining in PBMCs and TILs of ccRCC patients. Supplementary Figure S2: Imunoblotting for Cyclin D1 in sera of ccRCC patients.</p>