Contemporary approaches for vaccination and immunotherapy are often capable of eliciting strong T-cell responses against tumor antigens. However, such responses are not parallel to clinical tumor regression. The development of evasion mechanisms within tumor microenvironment may be responsible for poor therapeutic responses. We report here that constitutive or inducible expression of B7-H1, a B7 family molecule widely expressed by cancers, confers resistance to therapeutic anti-CD137 antibody in mice with established tumors. The resistance is accompanied with failure of antigen-specific CD8+ CTLs to destroy tumor cells without impairment of CTL function. Blockade of B7-H1 or PD-1 by specific monoclonal antibodies could reverse this resistance and profoundly enhance therapeutic efficacy. Our findings support that B7-H1/PD-1 forms a molecular shield to prevent destruction by CTLs and implicate new approaches for immunotherapy of human cancers.

The major effector cells for cellular adaptive immunity are CD8(+) cytotoxic T lymphocytes (CTLs), which can recognize and kill virus-infected cells and tumor cells. Although CTLs exhibit strong cytolytic activity against target cells in vitro, a number of studies have demonstrated that their function is often impaired within tumors. Nevertheless, CTLs can regain their cytotoxic ability after escaping from the tumor environment, suggesting that the milieu created by tumors may affect the function of CTLs. As for the tumor environment, the patho-physiological situation present in vivo has been shown to differ from in vitro experimental conditions. In particular, low pH and hypoxia are the most important microenvironmental factors within growing tumors. In the present study, to determine the effect of these factors on CTL function in vivo, we examined the cytolytic activity of CTLs against their targets using murine CTL lines and the induction of these cells from memory cells under low pH or hypoxic conditions using antigen-primed spleen cells. The results indicated that both cytotoxic activity and the induction of functional CTLs were markedly inhibited under low pH. In contrast, in hypoxic conditions, although cytotoxic activity was almost unchanged, the induction of CTLs in vitro showed a slight enhancement, which was completely abrogated in low pH conditions. Therefore, antigen-specific CTL functions may be more vulnerable to low pH than to the oxygen concentration in vivo. The findings shown here provide new therapeutic approaches for controlling tumor growth by retaining CTL cytotoxicity through the maintenance of higher pH conditions.

Summary Peripheral blood monocytes extravasate and differentiate into tissue macrophages to mediate effective local defence, but how tissue‐specific stimuli and environments may influence their functions remains unknown. Here, we found that peripheral blood monocytes gained the ability to produce granulocyte–macrophage colony‐stimulating factor (GM‐CSF) upon exposure to breast milk and differentiated into CD1+ dendritic cells (DCs) in the presence of exogenous interleukin‐4 (IL‐4) alone. This in vitro observation appeared physiologically relevant since macrophages that were freshly isolated from breast milk were also found to produce GM‐CSF spontaneously. Furthermore, in contrast to peripheral blood monocytes that differentiated into DCs only in the presence of both exogenous GM‐CSF and IL‐4, differentiation of breast milk macrophages into DCs was induced by incubation with exogenous IL‐4 alone. These IL‐4‐stimulated breast milk macrophages were efficient in stimulating T cells, suggesting their potential role in mediating T‐cell‐dependent immune responses in situ. On the other hand, unexpected expression of DC‐SIGN, a DC‐specific receptor for human immunodeficiency virus (HIV), even in unstimulated breast milk macrophages, may favour HIV infection, resulting in an increased risk of mother‐to‐infant vertical transmission of the virus via breast milk. Thus, tissue‐specific development of macrophages is often linked to effective local immunity, but may potentially provide an opportunity for a pathogen to spread and transmit.

Recent findings suggest that macrophage-tropic human immunodeficiency virus type 1 (HIV-1) produced in colostrum/early breast milk may hold a clue to determine the mechanisms of transmission of HIV-1 via breast-feeding. Here, we show that the majority of CD4(+) cells in the colostrum are CD14(+) macrophages expressing both chemokine receptors and DC-SIGN, a dendritic cell-specific receptor for HIV-1. The R5-type macrophage-tropic HIV-1 isolate NL(AD8) infected such breast-milk macrophages and caused them to secrete virus particles efficiently; however, the secreted virions showed only a weak transmissibility to their susceptible target, MAGIC-5 cells. When stimulated with interleukin-4, the breast-milk macrophages demonstrated a striking enhancement of expression of DC-SIGN and showed a strong capacity to transmit NL(AD8) virions to MAGIC-5 cells, which was specifically blocked by anti-DC-SIGN-specific antibody. These results suggest that HIV-1 virions captured by DC-SIGN, but not secreted cell-free virions, may be more efficiently transmitted to other compartments, such as the gastrointestinal tract, through acidic gastric juice.

Although adjuvant therapy for all patients may represent overtreatment, the findings of the present study suggest that, in the interest of fertility preservation, continuous postoperative hormonal treatment should be administered, at least to patients younger than 32 years. In patients who decline hormonal treatment, we recommend that they undergo follow-up for recurrence until 5 years after surgery.

The majority of human and rodent cancers display various antigens which could elicit cellular and humoral immune responses. Such immunity, however, often fails to prevent progressive growth of cancers. It has long been speculated that tumor antigens may not be presented in appropriate fashion, which subsequently fails to elicit a strong immune response. Recent studies, however, indicate that immunization by formulated tumor antigens or even transfer of pre-activated T lymphocytes also have limited impact on cancer growth despite the fact that these methods could often enhance immune responses in cancer patients. These findings imply that even afferent arm of immunity are strengthen, it is not necessarily being translated to tumor regression. It is possible that the development of evasion mechanisms in tumor microenvironment play a critical role in the resistance of therapeutic immune responses. Recent studies provide compelling evidence that human and rodent cancers develop evasion mechanisms by aberrantly expressing normal proteins, which are required for normal tissue homeostasis, to either build a microenvironment locally or reach other organs systemically. In this review, we will focus our discussion on two recently described molecules, B7-H1 and B7-H4, in the context of their roles in the evasion of tumor immunity and possible approaches for therapeutic manipulation.

Aim To investigate the accuracy and clinical value of an adhesion scoring system using transvaginal ultrasonography for endometriotic adhesion. Methods In this prospective observational study, we included 131 patients with endometriosis who underwent surgery. Before surgery, transvaginal ultrasonography and adhesion mapping were performed to determine the presence or absence of adhesions at 10 sites of the pelvis. Mapping accuracy was determined by comparing the mapping findings with the surgical findings. To determine the severity of pelvic adhesions, we developed an adhesion score (0–10). With the adhesion score, we assessed the effect of surgical adhesiolysis and evaluated the relationship between postoperative adhesions and infertility. Results Of the 10 sites assessed for adhesions, the most frequent site of adhesions was the site between the left ovary and the uterus (70.5%). The overall sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and accuracy of adhesion mapping were 80.4%, 86.1%, 78.8%, 87.2%, 5.79, 0.23 and 83.9%, respectively. The adhesion score in this system was significantly correlated with the adhesion‐related score in the revised American Society for Reproductive Medicine classification (R2 = 0.734). Surgical adhesiolysis yielded only about 30% improvement postoperatively. The adhesion score 1 month after surgery in the non‐in vitro fertilization (IVF) pregnancy group was significantly lower than that in the IVF pregnancy group (3.45 vs 5.21; P = 0.02). Conclusion Our adhesion scoring system allowed an accurate prediction of the pelvic adhesion status and may potentially be an indicator of postoperative adhesions and infertility.

A single prophylactic intratubal injection of MTX following laparoscopic linear salpingostomy is a safe and effective regimen for the prevention of PEP.