Impairment of lymphocyte function following yttrium-90 DOTATOC therapy

Abstract

The radiolabeled somatostatin analogue, yttrium-90 DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC), is currently applied to treat advanced somatostatin receptor-positive tumors, e.g., neuroendocrine tumors of the pancreas, lung or gut. However, effects of this treatment on antimicrobial immune responses are not yet defined. In 20 patients treated with DOTATOC, cellular in vitro immune function was determined. Their antimicrobial lymphocyte responses were assessed by lymphocyte transformation test and enzyme-linked immunospot-measuring lymphocyte proliferation and on a single cell level production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10)-prior to therapy, at day 1, day 7 and day 90 post-therapy. Proliferative lymphocyte responses and interferon-γ production after in vitro stimulation with microbial antigens were non-significantly suppressed at day 1 and significantly (p < 0.05) at day 7 versus pre-therapy. In vitro immune responses did not fully recover until day 90. In contrast, at day 1 interleukin-10 production was significantly (p < 0.05) increased. Taken together, we observed a decrease in pro-inflammatory immune responses after DOTATOC therapy. Patients with versus without bone metastases displayed significantly (p < 0.05) lower cellular immune responses toward several microbial antigens. Progressive disease and higher tumor burden could also be defined as factors associated with impaired immune function. Spearman correlation analysis indicated that cellular in vitro immunity was positively correlated with kidney function; better kidney function led to stronger immune responses. In conclusion, DOTATOC therapy caused a decrease in in vitro immune responses against microorganisms. The clinical impact needs to be evaluated in further studies.

Fig. 1

⁶⁸Ga DOTATOC positron emission tomography (PET) in 20 patients prior to ⁹⁰Y DOTATOC therapy. The images were arranged according to the tumor burden

Fig. 2

Cellular in vitro reaction toward mitogens and recall antigens in patients with somatostatin receptor-positive tumors receiving ⁹⁰Y DOTATOC therapy. Data represent mean and standard error of the mean (SEM), either pre-therapy (day 0, white bars), at day 1 (black bars), at day 7 (hatched bars) or at day 90 (striped bars) post-therapy. LTT mitogen responses (a, n = 18–20) and LTT antigen responses (b, n = 18–20) are given as counts per minute of ³H thymidine uptake (cpm), IFN-γ and IL-10 secretion to the ELISpot (c–f, n = 15–20) as spots per culture. The Wilcoxon matched pairs test was used for comparisons; the level of significance is indicated in comparison with day 0 (*p < 0.05, **p < 0.01). LTT lymphocyte transformation test, Aut. autologous, PHA phythohemagglutinin, ConA concanavalin A, PWM pokeweed mitogen, OKT3 anti-CD3 monoclonal antibody, PPD purified protein derivate (tuberculin), TET tetanus toxoid, CAN Candida albicans, HSV-1 Herpes simplex virus type 1, VZV Varicella zoster virus, INV-A influenza virus A, INV-B influenza virus B, IFN interferon, IL interleukin

Fig. 3

Immune responses toward microbial antigens are dependent on the presence of bone metastases in patients with ⁹⁰Y DOTATOC therapy. In vitro immune responses toward tetanus toxoid and Candida albicans were determined immediately prior to therapy (day 0), at day 1, day 7 and day 90 post-therapy. Patients with bone metastases (n = 13, black bars) displayed significantly lower immune responses as compared to patients without bone metastases (n = 7, white bars). Immunity was determined by lymphocyte transformation test as proliferation (LTT, a, b) and by ELISpot as interferon (IFN)-γ production per cell (c, d). The Mann–Whitney test was used for comparisons between patient groups (*p < 0.05, **p < 0.005). Not tested at day 7: n = 1 and at day 90: n = 2. Cpm: counts per minute; increment: The background reaction (autologous value) was subtracted from the specific reaction toward tetanus toxoid or Candida albicans

Fig. 4

Immune responses toward microbial antigens are dependent on the activity of the current therapy cycle in patients with ⁹⁰Y DOTATOC therapy. T cell proliferation as determined by lymphocyte transformation test (LTT) at day 7 post-therapy was significantly correlated with the activity of the current therapy cycle. Spearman correlation analysis is shown for immune responses toward tetanus toxoid (a) and Candida albicans (b) (n = 19 each). Cpm: counts per minute; increment: The background reaction (autologous value) was subtracted from the specific reaction toward tetanus toxoid or Candida albicans