High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome.

RATIONALE: Patients with acute coronary syndrome (ACS) predisposed to recurrent coronary events have an expansion of a distinctive T-cell subset, the CD4(+)CD28(null) T cells. These cells are highly inflammatory and cytotoxic in spite of lacking the costimulatory receptor CD28, which is crucial for optimal T cell function. The mechanisms that govern CD4(+)CD28(null) T cell function are unknown. OBJECTIVE: Our aim was to investigate the expression and role of alternative costimulatory receptors in CD4(+)CD28(null) T cells in ACS. METHODS AND RESULTS: Expression of alternative costimulatory receptors (inducible costimulator, OX40, 4-1BB, cytotoxic T lymphocyte associated antigen-4, programmed death-1) was quantified in CD4(+)CD28(null) T cells from circulation of ACS and stable angina patients. Strikingly, in ACS, levels of OX40 and 4-1BB were significantly higher in circulating CD4(+)CD28(null) T cells compared to classical CD4(+)CD28(+) T lymphocytes. This was not observed in stable angina patients. Furthermore, CD4(+)CD28(null) T cells constituted an important proportion of CD4(+) T lymphocytes in human atherosclerotic plaques and exhibited high levels of OX40 and 4-1BB. In addition, the ligands for OX40 and 4-1BB were present in plaques and also expressed on monocytes in circulation. Importantly, blockade of OX40 and 4-1BB reduced the ability of CD4(+)CD28(null) T cells to produce interferon-γ and tumor necrosis factor-α and release perforin. CONCLUSIONS: Costimulatory pathways are altered in CD4(+)CD28(null) T cells in ACS. We show that the inflammatory and cytotoxic function of CD4(+)CD28(null) T cells can be inhibited by blocking OX40 and 4-1BB costimulatory receptors. Modulation of costimulatory receptors may allow specific targeting of this cell subset and may improve the survival of ACS patients.

Impact of microscopic extranodal tumor deposits on the outcome of patients with rectal cancer.

PURPOSE: Microscopic mesorectal soft tissue extranodal deposits discontinuous with the primary tumor are identified in many rectal adenocarcinomas. Current guidelines consider them to be involved lymph nodes. We studied the impact of these deposits on the outcome of patients with rectal cancer. METHODS: This was a retrospective study, in which histology slides were reviewed from 55 patients whose resection specimens for rectal cancer were staged as Dukes C or Dukes B with extranodal deposits. Twenty-nine patients had extranodal deposits (19 males), and 26 control patients had lymph node involvement only (14 males). Patient outcome was analyzed in terms of local and systemic control and survival. RESULTS: Distant metastases were diagnosed earlier in patients with extranodal deposits (mean, 14 months) compared with controls (mean, 37 months; P = 0.001). On follow-up, 31.03 percent (9/29) from the extranodal deposit group developed liver metastases compared with 11.5 percent (3/26) of the control group (P = 0.08). Local recurrence was seen in 17.2 percent of patients from the extranodal deposit group and 3.8 percent of the control group (P = not significant). Cancer-related mortality was higher in the extranodal deposit group (16 vs. 7 patients; P = 0.09). The three-year actuarial survival was 48.27 percent in patients with extranodal deposits and 65.38 percent in those without. A significant association was noted between the number of extranodal deposits and intramural vascular invasion (P = 0.017), extramural vascular invasion (P = 0.039), perineural invasion (P = 0.039), and lymph node involvement (P = 0.008). CONCLUSION: These data suggest that extranodal deposit is a distinct form of metastatic disease in patients with rectal cancer. The association with vascular invasion and earlier development of metastases probably infers that a significant proportion of extranodal deposits may represent blood-borne spread. These tumor foci should be considered as indicators of poor prognosis.