Chemokine receptor 5 (CCR5) Δ32 base pair somatic gene deletions from PBM predict survival of patients with advanced stage (IV) melanoma

Abstract

10056 Background: Chemokines are a family of secreted chemotactic cytokines that function in leukocyte trafficking and activation. Chemokine receptor 5 (CCR5) is involved in CD4+ T-cell mediated immunity and dendritic cell (DC) activation. A 32 base pair (bp) deletion mutation on chromosome 3p21 result in a non-functional CCR5 with defective immunity. We hypothesized that CCR5Δ32 bp mutations would result in a diminished immune response to melanoma and maybe predictive of outcome of patients with advanced-stage disease. Methods: We identified 160 AJCC stage IV melanoma patients from our database whom had been made NED (no evidence of disease) by surgical resection. 105 (66%) had received active specific immunotherapy in phase I/II trials. Genomic DNA was extracted from peripheral blood mononuclear cells (PBM) and screened by PCR for the presence of CCR5Δ32 bp deletions. PCR products were sequenced to verify the result. Statistical analysis was performed by using Log-rank, Chi-square & Student’s t-test. Results: Of 160 patients, 100 (63%) were men. Ages ranged from 19–82 (median 47 yrs.). 46 (29%) patients had M1a, 48 (30%) Mlb and 66 (41%) Mlc stage of metastases prior to surgical resection. Median follow-up was 47.5 mos. 135 (84%) patients had wild-type (Wt)CCR5 gene; 21 (13%) had heterozygous (HtM) and 4(3%) had homozygous mutations (HoM). 5-yr survival was significantly higher for patients with CCR5 Wt than those with HtM or HoM deletions (55.6%±6.1% vs. 21.4%±10.8%, p=0.031). None of the 21 patients with HtM survived 10yrs. Multivariate analyses demonstrated only CCR5 gene status (Wt vs. HtM/HoM) as predictive of survival (p=0.007). Age (p=0.23), gender (p=0.38), and M stage (M1a vs. M1b/c) (p=0.31) were not important in the statistical model. When immunotherapy responses (+ vs. -) were included in the model both responses and CCR5 mutation status were significant (p=0.0021, p=0.0063 respectively). Conclusions: Our results suggest CCR5Δ32bp somatic mutations from PBM are present in advanced-stage melanoma patients and are highly predictive of survival. Functional CCR5 may be used as a selection factor for surgery but more importantly essential for either active immunotherapy or the natural immune response to be effective for these patients. No significant financial relationships to disclose.