CXCR6 and CCR5 localize T lymphocyte subsets in nasopharyngeal carcinoma.

The substantial T lymphocyte infiltrate found in cases of nasopharyngeal carcinoma (NPC) has been implicated in the promotion of both tumor growth and immune escape. Conversely, because malignant NPC cells harbor the Epstein-Barr virus, this tumor is a candidate for virus-specific T cell-based therapies. Preventing the accumulation of tumor-promoting T cells or enhancing the recruitment of tumor-specific cytotoxic T cells offers therapeutic potential. However, the mechanisms involved in T cell recruitment to this tumor are poorly understood. Comparing memory T cell subsets that have naturally infiltrated NPC tissue with their counterparts from matched blood revealed enrichment of CD8(+), CD4(+), and regulatory T cells expressing the chemokine receptor CXCR6 in tumor tissue. CD8(+) and (nonregulatory) CD4(+) T cells also were more frequently CCR5(+) in tumor than in blood. Ex vivo studies demonstrated that both receptors were functional. CXCL16 and CCL4, unique chemokine ligands for CXCR6 and CCR5, respectively, were expressed by the malignant cells in tumor tissue from the majority of NPC cases, as was another CCR5 ligand, CCL5. The strongest expression of CXCL16 was found on tumor-infiltrating cells. CCL4 was detected on the tumor vasculature in a majority of cases. These findings suggest that CXCR6 and CCR5 play important roles in T cell recruitment and/or retention in NPC and have implications for the pathogenesis and treatment of this tumor.

CD8(+) T-cell immunity against cancer-testis antigens develops following allogeneic stem cell transplantation and reveals a potential mechanism for the graft-versus-leukemia effect.

BACKGROUND: Allogeneic stem cell transplantation is associated with a powerful 'graft-versus-leukemia' effect that is generally considered to result from an alloreactive T-cell immune response. However, disease remission can also be observed after syngeneic transplantation and we investigated whether a T-cell immune response to cancer-testis antigens can be detected in patients in the post-transplant period. DESIGN AND METHODS: The T-cell immune response against cancer-testis antigens was studied in a cohort of 41 patients who underwent allogeneic stem cell transplantation for the management of acute myeloid leukemia or multiple myeloma. The cytokine secretion assay was combined with magnetic selection to allow detection of an interferon-gamma-secreting T-cell response to a panel of cancer-testis antigen peptides. RESULTS: A cancer-testis antigen-specific CD8(+) T-cell immune response was observed in the peripheral blood of five patients with an average magnitude of 0.045% of the CD8(+) T-cell repertoire. Four of these patients had undergone reduced intensity conditioning transplantation with alemtuzumab for the treatment of acute myeloid leukemia and three remain in long-term remission. T-cell immunity was focused against peptides derived from MAGE proteins and was markedly increased within the bone marrow. CONCLUSIONS: Functional cancer-testis antigen-specific CD8(+) T-cell immune responses develop in the early period following reduced intensity allogeneic stem cell transplantation and are preferentially localized to bone marrow. These immune responses are likely to contribute to the cellular basis of the graft-versus-leukemia effect.

Differential pattern of CD4+ and CD8+ T-cell immunity to MAGE-A1/A2/A3 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma.

The factors that determine progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma are unclear but may include the breakdown of immune surveillance. Cancer testis antigens (CTAgs) are expressed by the majority of myelomas and MGUS tumors and are a potential immune target. We have characterized CD4(+) and CD8(+) T-cell immune responses to MAGE-A1/A2/A3 in these patients. CD4(+) T-cell immunity to MAGE proteins is stronger and more frequent in MGUS compared with myeloma with a predominantly CD45RA(-)CCR7(-) effector memory profile and cytotoxicity against MAGE-positive cell lines. In contrast CD8(+) T-cell immune responses were present almost exclusively in patients with multiple myeloma, correlating with disease, with a CD45RA(+)CCR7(-) memory phenotype, localizing poorly to the bone marrow but were able to lyse myeloma cell lines in vitro. This suggests that the CD4(+) CTAg-specific immune response may play a role in controlling tumor growth, whereas the efficacy of the CD8(+) T-cell response appears to be limited in vivo. Despite this, patients with evidence of a CTAg-specific immune response had a 53% reduction in mortality over a median follow-up of 4 years. These findings have important implications for clinical approaches to CTAg-specific immunotherapy in patients with cancer.

Functional HY-specific CD8+ T cells are found in a high proportion of women following pregnancy with a male fetus.

Recent studies have demonstrated that fetal cells can be detected in the maternal circulation during virtually all human pregnancies. These fetal cells can engraft and may be isolated for many decades after pregnancy, leading to a state that may be maintained by the passage of pregnancy-associated progenitor cells. The clinical consequences of fetal cell microchimerism are unclear but may be potentially detrimental or valuable to the mother. One possibility is the generation of an alloreactive immune response by the mother to antigens expressed by the fetus; for example, the HY protein encoded by the Y chromosome. To test this we have screened a cohort of women with a range of parity histories within 8 yr of their last pregnancy for the presence of an HY-specific CD8+ T-cell response. Fluorescent HLA-peptide (HY) tetramers were used to stain short-term T-cell cultures from these women for analysis by flow cytometry. Responses were detected in 37% of women with a history of pregnancies that produced males, and this value rose to 50% in women with two or more pregnancies that produced males. HY-specific CD8+ T cells also could be detected directly in the peripheral blood of women with a history of at least two pregnancies that produced males. These HY-specific CD8+ T cells produced interferon gamma (IFNG) following peptide stimulation, demonstrating their functional capacity. In conclusion, our data indicate that alloreactive CD8+ T cells are generated frequently following normal pregnancy and retain functional capability for years following pregnancy.