Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, a cancer-associated retinopathy antigen, possibly related with a better prognosis in a paraneoplastic syndrome

Abstract

Cancer-associated retinopathy (CAR) is a rare paraneoplastic syndrome, and the recoverinspecific autoantibody is suggested to contribute to the pathogenesis of retinopathy, including apoptosis of retinal cells. Because it is known that CAR + cancer patients have a preferable prognosis, we hypothesized that aberrantly expressed recoverin in cancer cells can become a target of cytotoxic T lymphocytes (CTL). Here we tested nine recoverin-derived HLA-A24-binding peptides for their capacity to elicit antitumor CTL. We observed recoverinspecific CTL responses in two HLA-A24 + CAR + cancer patients. In addition, the CTL responses were obtained from three of ten CARcancer patients and two of six healthy individuals. The CTL precursor frequency of CAR + cancer patients and that of CARcancer patients was higher than that of healthy individuals. Of nine recoverin peptides, R49 (QFQSIYAKF), R49.2 (QFQSIYAKFF), and R64 (AYAQHVFRSF) were discovered to induce the peptide-specific CTL. Taken together, our present data suggest that peripheral activation of recoverin-specific antitumor CTL is likely to contribute to the preferable prognosis of CAR + cancer patients. Moreover, in cases other than CAR + cancer patients, recoverin may offer the opportunity to design epitope-based immunotherapeutic approaches for treating HLA-A24 + cancer patients with a recoverin-expressing tumor.

Clonal diversity of cytotoxic T lymphocytes that recognize autologous oral squamous cell carcinoma

“…Previously, we reported autologous cancer cell line and CTL pairs from several epithelial malignancies [3,[12][13][14][15]. By analysis of those CTLs, we succeeded in isolating novel cancer-associated antigens [5,16], as well as antigenic peptides by reverse immunogenetic analysis [7,[17][18][19]. With this progress, we started a clinical trial for cancer vaccine therapy with an antigenic peptide derived from one of the cancer-associated antigens, survivin [20].…”

“…To obtain the CTL clones, standard limiting dilution was performed as described previously [7]. Briefly, series of diluted CTLs were incubated with 1ϫ10 4 100 Gy-irradiated LG2-EBV (a kind gift from Dr. B. J. Eynde, Ludwig Institute for Cancer Research, Brussels, Belgium) and 5ϫ10 4 allogeneic PBMCs as feeder cells in 200 l of AIM-V medium supplemented with 10% HS, the anti-CD3 Ab (40 ng/ml) (BD), and 100U/mL rIL-2 in 96-well round plates.…”

Long-term survival of a patient with small cell lung cancer associated with cancer-associated retinopathy

“…However, given the supporting experimental data that have been accumulating, it is believed that cytotoxic T-lymphocytes (CTL) rather than anti-recoverin autoantibody play a major role in causing retinal cell apoptosis and suppression of SCLC [10,11]. Therefore, autoantibodies are regarded as a surrogate marker of cellular immunity, which could explain the existence of the anti-recoverin antibody-negative CAR syndrome [12][13][14].…”

“…Conversely, it is has been suggested that patients with CAR had a better prognosis than those without CAR [17,18]. Maeda et al referred to the favorable prognosis of patients with CAR by describing that one of two SCLC patients with CAR in their study continued to lead an ordinary life for several years at that time [10]. They reported that vaccination with recoverin induces recoverin-specific CTL and tumor cell regression in experimental mouse model grafted recoverin-expressing tumor cells and that elevated anti-recoverin antibody titers strongly correlated with retinal cell dysfunction [11].…”

Pathogenesis and treatment of paraneoplastic neurologic syndrome

“…To date, these cells are involved in the development of MS [73,74], polymyositis [72], inclusion body myositis [75], Rasmussen's syndrome [76,77], progressive multifocal leukoencephalopathy [78] and paraneoplastic neurologic syndrome including paraneoplastic cerebellar degeneration with antiYo antibodies [54,79], antiHu syndrome [65,66,80], cancerassociated retinopathy [81] and possibly antiMa2 syndrome [82].…”