Interleukin (IL)-21 modulates T-cell-associated, B-cellassociated, and natural killer cell-associated immunity.

Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other therapeutic approaches, e.g. chemotherapy, cytokine therapies, anti-OX40 therapy, and peptide or DC vaccines. However, the adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer has not been fully evaluated. In this report, effector T cells were generated in vitro by anti-CD3/anti-CD28 activation of tumor-draining lymph node (TDLN) cells and used in an adoptive immunotherapy model. While T cells or anti-4-1BB alone showed no therapeutic efficacy in mice bearing macroscopic 10-day pulmonary metastases, T cells plus anti-4-1BB mediated significant tumor regression in an anti-4-1BB dose dependent manner. Mice bearing microscopic 3-day lung metastases treated with T cells alone demonstrated tumor regression which was significantly enhanced by anti-4-1BB administration. NK cell depletion abrogated the augmented therapeutic efficacy rendered by anti-4-1BB. Cell transfer between congenic hosts demonstrated that anti-4-1BB administration increased the survival of adoptively transferred TDLN cells. Using STAT4-/- mice, we found that modulated IFNγ secretion in wt TDLN cells after anti-CD3/CD28/4-1BB activation in vitro was lost in similarly stimulated STAT4-/- TDLN cells. Additionally, anti-4-1BB administration failed to augment the therapeutic efficacy of T cell therapy in STAT4-/- mice. Together, these results indicate that administered anti-4-1BB mAb can serve as an effective adjuvant to augment the antitumor reactivity of adoptively transferred T cells by recruiting the host NK cells; increasing the persistence of infused effector T cells, and modulating the STAT4 molecular signaling pathway.

Purpose Postoperative diarrhea, including high-output stoma (HOS), frequently occurs after colorectal surgery; its risk factors and clinical implications on subsequent complications remain unknown. This study aimed to evaluate the risk factors and clinical implications of postoperative diarrhea after primary colorectal cancer (CRC) surgery. Methods This prospective observational study included patients with CRC who underwent radical surgery at six hospitals between June 2016 and December 2017. The patients were categorized into three groups (non-stoma, colostoma, and ileostoma groups). Results A total of 178 patients participated in the study. In the non-stoma group, the incidence of postoperative diarrhea was 18.4% (27/147). The incidence of HOS was 28.6% (4/14) in the ileostoma group, and 0% in the colostoma group. Multivariable analyses of the incidence of diarrhea in the non-stoma group indicated that habitual smoking and hypertension were significantly associated with postoperative diarrhea (P = 0.012 and P = 0.0274, respectively). Postoperative diarrhea was more likely to occur in patients with rectal cancer than in those with colon cancer (P = 0.0501). In the non-stoma and ileostoma groups, the probability of the occurrence of other complications with Clavien–Dindo (C-D) grades II or higher was significantly higher in patients with C-D grade I diarrhea, including HOS, than in patients without diarrhea (39.3% vs. 14.6%, P = 0.0061). Conclusions Smoking and hypertension are the independent predictors of postoperative diarrhea after an elective CRC surgery. Rectal cancer surgery seems to be associated with postoperative diarrhea more than colon cancer surgery does. Mild postoperative diarrhea may lead to more severe complications.

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