Regulation Of Antitumor Immunity Research Articles

P1.05-020 Opposing Prognostic Roles of CD73 and A2A Adenosine Receptor in Non-Small-Cell Lung Cancer

CD73 (otherwise known as ecto-5’-nucleotidase) is an important molecule in the adenosine pathway because it generates adenosine by enzymatically dephosphorylating extracellular AMP, which results in immunosuppressed niche within the tumor microenvironment. A2A adenosine receptor (A2AR) acts as a predominant receptor for adenosine in immune cells and can also be expressed in lung tumor cells. However, the clinical impact of the adenosine pathway in non-small-cell lung cancer (NSCLC) has yet to be uncovered, although the pathway has been shown to have a pivotal role in the regulation of anti-tumor immunity and is considered as one of the promising future treatment targets. We investigated CD73 and A2AR protein expression profiles using immunohistochemistry in tissue microarrays containing 642 resected NSCLC specimens. The expression levels were assessed using the H-score method that ranged from 0 to 300, and cutoffs were determined using the minimum P-value method for overall survival (OS). The associations between their expression levels and clinicopathological and molecular characteristics as well as patients’ prognoses were retrospectively analyzed. The median age of patients was 68 years old (range, 23–88) and 440 (68.5%) patients were male. 438 (68.2%) patients had smoking history and 420 (65.4%) patients had adenocarcinoma histology. Significantly higher expression of both CD73 and A2AR was observed in female than male, in never smokers than ever smokers, and in adenocarcinomas than squamous cell carcinomas. Among adenocarcinomas, both high CD73 and A2AR expression were significantly associated with TTF-1 positivity and EGFR mutations. ALK-positive adenocarcinomas showed significantly higher expression levels of CD73 than ALK-negative tumors. High CD73 expression was an independent indicator of a poor prognosis for NSCLC patients in multivariate Cox regression analyses for OS (hazard ratio (HR), 2.19; 95% confidence interval (CI), 1.38–3.47) and disease-specific survival (DSS) (HR, 2.97; 95% CI, 1.78–4.95). Contrary, high A2AR expression was an independent favorable predictor of prognosis for OS (HR, 0.69; 95% CI, 0.49–0.97) and DSS (HR, 0.51; 95% CI, 0.33–0.79). Among adenocarcinomas, high CD73 expression was an independent poor prognostic marker for OS (HR, 2.73; 95% CI, 1.61–4.63) and DSS (HR, 4.57; 95% CI, 2.54–8.23), whereas high A2AR expression was an independent favorable prognostic marker for DSS (HR, 0.56; 95% CI, 0.32–0.98). Both CD73 and A2AR expression was associated with TTF-1-positive and EGFR-mutant adenocarcinoma. Nonetheless, they had opposing prognostic significance in resected NSCLC.

Rationale for the Combination of Dendritic Cell-Based Vaccination Approaches With Chemotherapy Agents.

Owing to their central role in the initiation and regulation of antitumor immunity, dendritic cells (DCs) have been widely tested for use in cancer immunotherapy. Despite several encouraging clinical applications, existing DC-based immunotherapy efforts have yielded inconsistent results. Recent work has identified strategies that may allow for more potent DC-based vaccines, such as the combination with antitumor agents that have the potential to synergistically enhance DC functions. Selected cytotoxic agents may stimulate DCs either by directly promoting their maturation or through the induction of immunogenic tumor cell death. Moreover, they may support DC-induced adaptive immune responses by disrupting tumor-induced immunosuppressive mechanisms via selective depletion or inhibition of regulatory subsets, such as myeloid-derived suppressor cells and/or regulatory T cells (Tregs). Here, we summarize our current knowledge on the capacity of anticancer chemotherapeutics to modulate DC phenotype and functions and the results of ongoing clinical trials evaluating the use of DC-based immunotherapy in combination with chemotherapy in cancer patients.

Abstract SY31-02: The interplay of radiotherapy with the tumour microenvironment: Novel opportunities to overcome adaptive resistance

Abstract SY31-02: The interplay of radiotherapy with the tumour microenvironment: Novel opportunities to overcome adaptive resistance

Abstract OT1-01-07: nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC)

Abstract Background: Nivo is an inhibitory antibody against programmed death receptor-1 (PD-1), a regulator of antitumor immunity. Nivo is approved for treatment of unresectable or metastatic melanoma and disease progression (PD) following ipilimumab or, in BRAF V600 mutation–positive melanoma, following a BRAF inhibitor, and for metastatic squamous non-small cell lung cancer (NSCLC) following PD during or after platinum-based chemotherapy. Nivo and other immune checkpoint inhibitors are also being investigated in other tumor-types. nab-P is a novel taxane formulation and does not require prophylaxis with immunosuppressive steroids. It has demonstrated superior efficacy over control regimens in phase III studies of MBC, pancreatic cancer, and NSCLC. This open-label, 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab-P in 3 cancer types (2 arms/disease): MBC, advanced NSCLC (+ carboplatin), and advanced pancreatic cancer (± gemcitabine). The study design for the MBC portion is described below. Methods: Eligibility criteria include histologically/cytologically confirmed HER2-negative MBC; 1 prior chemotherapy for MBC, including an anthracycline unless clinically contraindicated; no relapse < 12 months after taxane adjuvant therapy; measurable disease by RECIST v1.1; ECOG performance status 0-1; adequate organ function; and preexisting peripheral neuropathy grade < 2. Patients (pts) with MBC will be treated in 2 arms: nab-P 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus Nivo 3 mg/kg on days 1 and 15 starting at cycle 3 or nab-P 260 mg/m2 on day 1 of each 21-day cycle plus Nivo 5 mg/kg on day 15 starting at cycle 3. Pts will be treated until PD or allowed to continue treatment beyond RECIST v1.1–defined PD if they continue to meet study eligibility; do not have rapid PD or clinical deterioration or unacceptable toxicities; and can benefit from continuation of study treatment in the treating physician's opinion and will not delay an imminent intervention to prevent serious complications of PD. The primary endpoints of the study are the number of pts with dose-limiting toxicities (DLTs) in each treatment arm (part 1) and the percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to a TEAE (parts 1 and 2). Part 1 of the study will assess whether the starting dose of Nivo is deemed safe (≤ 1 DLT in 6 pts); otherwise, the Nivo dose will be de-escalated and assessed in a new cohort at the next lower dose level. The Nivo dose in combination with nab-P deemed safe in a treatment arm may be further assessed in part 2 of the study, with enrollment expanded to an additional ∼ 14 pts/arm (total of 20 Nivo-treated pts/arm). Secondary study endpoints include TEAEs leading to dose reduction, delay, interruption, or treatment discontinuation; progression-free survival; overall survival; disease control rate; overall response rate; and duration of response (per RECIST v1.1). Exploratory endpoints include tumor-associated PD-L1 expression, modulation of immune activation in the tumor and peripheral blood in response to Nivo treatment, Nivo serum levels, and development of anti-globulin antibodies. ClinicalTrials.gov identifier NCT02309177. Citation Format: Waterhouse D, Gutierrez M, Bekaii-Saab T, DeRosa W, Wainberg Z, George B, Duval Fraser C, Ko A, Pierce DW, Stergiopoulos S, Soliman H. nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-07.

The Role of Tumor/Dendritic Cell Interactions in the Regulation of Anti-Tumor Immunity: The Good, the Bad, and the Ugly

Since the discovery of dendritic cells (DCs) by Ralph Steinmanand Zanvil Cohn 40years ago (1), the role of these cells as criticalregulators of immune tolerance versus activation has emerged asone of the most fundamental concepts in the field of immunol-ogy. Serving as a link between the innate and adaptive immunesystems, DCs exhibit sensitive immune surveillance capabilitiesthat enable their acquisition of antigens from a variety of sourcesin peripheral tissues, and they possess unique sensory propertiesand antigen processing machinery that enable their transforma-tion into potent antigen-presenting cells (APCs). Importantly, theoutcome (immune tolerance versus activation) of antigen pre-sentation to T cells by DC is dependent on the maturation andactivation state of the DC, and significant efforts over the last 20CyearshavethereforefocusedonunderstandingfactorsthatregulateDC maturation and activation. While their role in self-toleranceand the activation of T cell immunity to foreign pathogens haslong been appreciated, more recently DCs have also been shownto play important roles in the regulation of anti-tumor immuneresponses. Since this time, considerable efforts have been placedon understanding many facets of tumor-associated DC,including:the induction, regulation, and maintenance of anti-tumor immu-nity by DC; tumor-associated interference with these processes tosubvert anti-tumor immunity; and the application of this knowl-edgetodeveloptherapeuticstrategiesforimprovingDC-mediatedanti-tumor immune responses. In this collection of articles, wehighlight our current understanding of the role played by DCin anti-tumor immunity and focus attention on important ques-tions that remain to be answered in the field as we aim to improvethe immunogenicity of tumor-associated DC and the outcome ofDC-mediated anti-tumor immune responses in the future.We begin this research topic with an Opinion article by RolfZinkernagel (2) and a responding Commentary from Anne Hos-malin (3), who offer opposing views on cross-presentation oftumor antigen by DC that we believe will generate interestingand thoughtful discussion. These articles are followed by a con-tribution from Schiavoni et al. (4) reviewing the major subsets ofDC that have been implicated in cross-presentation and the roleof type I IFN in enhancing DC-mediated cross-priming of anti-tumor CD8C T cell responses. Research topic co-editor KristianHargadon then reviews the various levels at which tumor cells,tumor-derived factors, and tumor-associated cells in the milieuof the tumor microenvironment can interfere with DC function(5). Mechanistic insights into tumor-altered differentiation of DCprecursors, tumor-associated suppression of DC maturation andactivation, and tumor-induced development of regulatory DCwith immunosuppressive function are highlighted, as are recentimmunotherapeutic strategies that have been designed to pre-vent or overcome tumor-associated DC dysfunction and enhancethe quality of anti-tumor immune responses. Co-editor Timo-thy Bullock further examines the metabolic changes that occurin DC during their maturation and discusses how dysregulatedmetabolism, particularly at the level of glycolysis and fatty acidmetabolism,intumor-associatedDCmayalsoimpedematurationand contribute to the diminished immune stimulatory functionof these cells (6). The impact of tumors on DC maturation isalso explored by Dudek et al. (7), who describe the complex-ity of DC maturation status in the context of tumors, wherethe typical dichotomy of immature versus mature DC that reg-ulate immune tolerance versus activation against clearly “self” or“non-self” antigen is less obvious. The authors describe a contin-uum of DC maturation states reported in the context of tumorsthat include not only the classical immature, tolerogenic DCand mature, immunogenic DC but also semi-mature DC whichexpress low or even moderate levels of costimulatory moleculesbut which produce minimal stimulatory cytokines and there-fore potentiate either tolerogenic or pro-tumorigenic responses.Studies that have identified factors (cytokines/chemokines, celldeath modalities, and cancer cell-derived danger signals) regulat-ing tumor-associated DC function are highlighted, as is the abilityof anti-cancer therapeutic agents to influence and modulate thematuration states of DC.Additional discussion of this topic is pro-videdbyOttandBhardwaj(8),whospeculatehowtumorcelldeathresulting from MAPK pathway inhibition might enhance cross-presentation by DC in BRAF

Abstract 1629: Semaphorin 4D has a dual role in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Abstract Pancreatic ductal adenocarcinoma (PDAC) contains a dense, fibrotic tissue called stroma. The stroma, consisting of connective tissue, fibroblasts, leukocytes, and blood vessels, accompanies most solid tumors, but its extent and compactness are exceptional in PDAC. A detailed understanding of cells contained in the stroma is an essential step for control of PDAC. In this study, we focused on the molecule called Semaphorin4D (Sema4D), which is involved in tumor-stromal signal transduction pathways in several kinds of cancer, and analyzed its expression patterns and functions in PDAC. First, we examined the expression of Sema4D and its receptor, plexin B1, in surgically resected specimens of human PDAC, and also the effect of Sema4D stimulation using human pancreatic cancer cells in vitro. Immunohistochemical staining revealed that Sema4D was expressed on the tumor-infiltrating lymphocytes. On the other hand, plexin B1 was expressed on the cancer cells. The overexpression of Sema4D was found to be significantly correlated with invasive or metastatic clinical factors, and poor prognosis in patients with PDAC. Also, stimulation by Sema4D caused a significant increase in the invasiveness of pancreatic cancer cells measured by matrigel invasion chambers. The enhanced-cell invasiveness induced by Sema4D could be inhibited by knockdown of plexinB1, suggesting that blockade of plexinB1 might diminish the invasive potential of pancreatic cancer cells. Next, we analyzed the tumor growth of mouse pancreatic cancer cells in vivo using wild type (WT) and Sema4D Knock Out (KO) mice. In a breast cancer model, it was reported that tumor growth and vascularization in the tumor were severely impaired in Sema4D KO mice. However, in contrast, in pancreatic cancer, tumor growth and vessel formation in tumors were not impaired in Sema4D KO mice. In fact, tumor growth was accelerated in Sema4D KO mice. We performed further analysis and found that there were fewer infiltrating CD8+ T cells in tumors of Sema4D KO mice compared to tumors of WT mice. It has been reported that Sema4D has an immunoregulatory function through another receptor, CD72, in the immune system, and that Sema4D KO mice have functional defects in their immune system. These results suggest that Sema4D has multiple functions in controlling tumor formation, invasiveness, vascularization, and anti-tumor immunity, and that its role in the regulation of anti-tumor immunity is more apparent in the pancreatic cancer model. Our findings suggest that Sema4D can play a dual role in PDAC. One role is to enhance tumor invasiveness through plexinB1 on tumor cells, while the other is to regulate the immune response to tumor through CD72 on lymphocytes. Our findings provide insight into new molecular targets for the development of treatments for PDAC. Citation Format: Shingo Kato, Kensuke Kebota, Noritoshi Kobayashi, Kunihiro Hosono, Seitaro Watanabe, Yusuke Sekino, Takamitsu Sato, Shin Maeda, Atsushi Nakajima. Semaphorin 4D has a dual role in the tumor microenvironment of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1629. doi:10.1158/1538-7445.AM2013-1629

Abstract 4985: Expression of FasL on the tumor endothelium establishes a selective immune barrier in ovarian cancer.

Abstract There is an intimate relationship between angiogenesis and immune suppression in cancer, and anti-angiogenesis strategies can complement cancer immunotherapy. Previous research has implicated the tumor endothelium as a critical regulator of anti-tumor immunity, and our current work establishes a new role for the tumor endothelium as a critical barrier to T cell infiltration mediated through FasL. FasL is an important regulator of immunity and apoptosis, and we have found that, in contrast to the endothelium of normal tissues, the endothelium of multiple tumor types expressed FasL. FasL expression was restricted to tumor islets, and hypoxic tumor cell-conditioned media induced FasL on endothelial cells in vitro. Combination treatment with proangiogenic growth factors VEGF and PGE2 induced endothelial FasL expression in vitro, and COX1 and VEGF expression were associated with endothelial expression of FasL in ovarian cancer patients. Combinatorial blockade of VEGF and COX enzymes reduced endothelial FasL expression in mice, decreased tumor volume, and increased the CD8/FoxP3 ratio. In patients, low endothelial FasL expression was associated with a high CD8/Foxp3 ratio and increased survival. We found that endothelial FasL contributes to an unfavorable CD8/FoxP3 ratio through preferential killing of tumor-reactive CD8 T cells relative to Tregs. Increased intratumoral CD8/FoxP3 ratio was also observed in tumors grown on gld and lpr mice, but tumor growth was not robustly inhibited in these mice. Tumor control was dependent on the induction of an anti-tumor immune response, and CD8 depletion reversed the effects of VEGF and COX blockade. Additionally, combinatorial VEGF and COX blockade, tumors grown on gld mice, or the use of anti-FasL antibody all enhanced infiltration of adoptively transferred anti-tumor T cells and reduced apoptosis of transferred cells. Together, this work lends mechanistic insights into existing observations regarding T cells and tumor angiogenesis, and provides additional evidence for the paradigm that angiogenesis and immune suppression are intricately linked. Additionally, this work provides new strategies for cancer immunotherapy that may result in superior tumor control in patients. Citation Format: Greg Motz, George Coukos. Expression of FasL on the tumor endothelium establishes a selective immune barrier in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4985. doi:10.1158/1538-7445.AM2013-4985 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Invariant NKT cells as novel targets for immunotherapy in solid tumors.

Natural killer T (NKT) cells are a small population of lymphocytes that possess characteristics of both innate and adaptive immune cells. They are uniquely poised to respond rapidly to infection and inflammation and produce cytokines that critically shape the ensuing adaptive cellular response. Therefore, they represent promising therapeutic targets. In cancer, NKT cells are attributed a role in immunosurveillance. NKT cells also act as potent activators of antitumor immunity when stimulated with a synthetic agonist in experimental models. However, in some settings, NKT cells seem to act as suppressors and regulators of antitumor immunity. Here we briefly review current data supporting these paradoxical roles of NKT cells and their regulation. Increased understanding of the signals that determine the function of NKT cells in cancer will be essential to improve current strategies for NKT-cell-based immunotherapeutic approaches.

P1-01-05: Conditioning by the Tumor Environment Turns Invariant Natural Killer T Cells into Negative Regulators of Anti-Tumor Immunity Elicited by Treatment.

Abstract Background: Local suppression in the tumor microenvironment remains an important obstacle to success of immune-based therapy. We have previously shown in the 4T1 model of metastatic breast cancer that combination radiotherapy (RT) to the primary tumor and CTLA-4 blockade can elicit a robust anti-tumor effector response that can inhibit metastases and prolong survival. However, complete cure and long-term memory was seen in only a small fraction of mice, prompting us to investigate new ways to improve the response elicited by treatment. iNKT cells are known to be powerful regulators of tumor immunity as a result of their ability to rapidly secrete a broad range of cytokines, but the mechanisms regulating their switch from a stimulatory to a regulatory role remain poorly defined. We have previously shown that iNKT cells negatively regulate the response to treatment with RT and CTLA-4 blockade in 4T1 tumor-bearing mice (Clin Cancer Res 15:597, 2009). Here, we test the novel hypothesis that conditioning of iNKT cells to perform this regulatory role occurs within the tumor microenvironment. Specifically, we address whether 4T1 tumor cells, directly or indirectly, promote iNKT cell regulatory phenotype. Methods: For in vitro experiments, 4T1 tumor or LPS-matured bone marrow-derived dendritic cells (BMDC) were loaded with α-galactosylceramide and used to stimulate the NKT DN32.D3 hybridoma cells. In some wells, BMDCs were supplemented with 4T1 conditioned media or loaded with tumor lysates from 4T1 cells. For in vivo experiments, wild-type and iNKT-deficient mice were inoculated s.c with 4T1 cells for enumeration of DCs on immunostained sections. Phenotypic profile of DCs within tumor and draining lymph nodes were assessed by flow cytometry. Results: 4T1 cells are positive for CD1d by real-time RT-PCR; surface CD1d were barely detectable by flow cytometry but sufficient to induce activation of DN32.D3 cells when irradiated 4T1 cells were loaded with α-GalCer. BMDC supplemented with conditioned media from untreated or irradiated 4T1 cells, or loaded with tumor lysates from irradiated 4T1 cells were also able to activate DN32.D3 cells, and this effect was partially inhibited by blocking CD1d mAb (1B1) in a dose-dependent manner. In vivo, we found that iNKT-deficient mice showed significantly (p=0.04) higher densities of tumor infiltrating DCs than wild type mice. Moreover, DC in tumor and tumor-draining lymph nodes expressed markers of maturation in the absence but not presence of iNKT cells. Conclusion: Results indicate that a 4T1 derived factor, possibly a lipid antigen that can be presented directly by tumor cells themselves or indirectly by BMDCs induces activation of iNKT cells in vitro. In vivo, data suggests that iNKT cells downregulate the response to treatment by controlling the population of DC present in the tumor and draining lymph nodes. Since DC are essential for cross-presentation of the tumor antigens released by RT-induced cell death, reduced DC numbers may impair the activation of anti-tumor T cells. Supported by DOD Postdoctoral Award W81XWH-10-1- Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-05.

Suppression of the maturation and activation of the dendritic cell line DC2.4 by melanoma-derived factors

Dendritic cells play critical roles in both innate and adaptive immunity, and their numerous functions are tightly linked to their maturation and activation status. Here, we characterize the murine dendritic cell line DC2.4 as a model for studying dendritic cell maturation and activation, and we evaluate the influence of melanoma tumor cells on these processes. Exposure of DC2.4 cells to the Toll-like receptor ligand lipopolysaccharide induces both maturation and activation of these cells, characterized by upregulation of costimulatory molecule expression and proinflammatory cytokine/chemokine production. This maturation and activation is suppressed by soluble factors derived from both the highly tumorigenic B16-F1 and the poorly tumorigenic D5.1G4 murine melanoma cell lines. Interestingly, the extent of DC2.4 immunosuppression by these melanomas correlates with their tumorigenicity, suggesting a potentially vital role for dendritic cell/tumor cell interactions in the regulation of anti-tumor immunity and tumor outgrowth.

Variation of Tumor-Infiltrating Lymphocytes in Human Cancers: Controversy on Clinical Significance

Tumors develop and progress under the influence of a microenvironment comprising a variety of immune cell subsets and their products. Recent studies have shown that tumor-infiltrating lymphocytes (TILs) are not randomly distributed, but organized to accumulate more or less densely in different regions within tumors, and interact with each other. Substantial evidence has suggested that not only CD8(+) and/or CD4(+) αβ T cells but also other lymphocyte subsets, including γδ T cells, B cells, NK cells, and NKT cells, infiltrate tumor tissues in variable quantities and play a key role in the regulation of antitumor immunity. In this article, we summarize available information regarding the diversity and composition of TILs, which may positively or negatively affect tumor growth and patient clinical outcomes. The clinical significance of TILs in human cancers remains unclear and is a subject of considerable controversy; largely due to the lack of functional data for TILs, as well as due to enormous variability of TILs in different tumors. A great deal more functional data about TILs needs to be obtained for individual tumors before TILs can be considered as a prognostic parameter in human cancers.

The role of CD200 in immunity to B cell lymphoma

CD200 is a transmembrane protein broadly expressed on a variety of cell types, which delivers immunoregulatory signals through binding to receptors (CD200Rs) expressed on monocytes/myeloid cells and T lymphocytes. Signals delivered through the CD200:CD200R axis have been shown to play an important role in the regulation of anti-tumor immunity, and overexpression of CD200 has been reported in a number of malignancies, including CLL, as well as on cancer stem cells. We investigated the effect of CD200 blockade in vitro on a generation of CTL responses against a poorly immunogenic CD200+ lymphoma cell line and fresh cells obtained from CLL patients using anti-CD200 mAb and CD200-specific siRNAs. Suppression of functional expression of CD200 augmented killing of the CD200+ cells, as well as production of the inflammatory cytokines IFN-gamma and TNF-alpha by effector PBMCs. Killing was mediated by CD8+ cytotoxic T cells, and CD4+ T cells play an important role in CD200-mediated suppression of CTL responses. Our data suggest that CD200 blockade may represent a novel approach to clinical treatment of CLL.

Regulation of anti-tumor immunity by p53 (95.2)

Abstract Several pro-apoptotic molecules play an essential role in regulating oncogenesis as well as T-cell expansion during immune responses. Tumor suppressor molecule p53 regulates DNA repair, genomic integrity, cell proliferation and apoptosis. Mutations of P53 pathway is the most common genetic aberration in human tumors and as many as 50% of all the human tumors contain mutation in p53 pathway. Mice lacking p53 preferentially develops T-cell lymphomas and is susceptible to induced autoimmune dieases, suggestting a role for p53 in regulation of T cell responses. We found that p53 acts as a negative regulator of immune responses by inducing apoptosis and inhbiting T-cells proloiferation during immune responses. Furthermore, p53-deficient mice generates a robust anti-tumor cytotoxic T-cell responses and reject an implanted immunogenic tumor. These findings demonstrate an essential role of p53 in generating anti-tumor T-cell responses and suggest that a careful immunomodulation should be considered to achieve optimum results if p53 pathway is potential target of cancer chemotherapy.

B7‐H3 and Its Role in Antitumor Immunity

B7-H3 is one of the most recently identified members of the B7/CD28 superfamily of costimulatory molecules serving as an accessory modulator of T-cell response. Recently, B7-H3 expression has been reported in several human cancers indicating an additional function of B7-H3 as a regulator of antitumor immunity. However, its precise physiologic role is still elusive, because both stimulatory and inhibitory capacities have been demonstrated. This paper summarizes the available data on B7-H3 in the regulation of T-cell response focusing on its potential role in antitumor immunity.

Reciprocal activating interaction between 6‐sulfo LacNAc+ dendritic cells and NK cells

Dendritic cells (DCs) display an extraordinary capacity to induce T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Additional findings indicate that DCs may also play a crucial role for the activation of natural killer (NK) cells, which are important effectors in innate antitumor immunity. However, studies investigating the interaction between native human DCs and NK cells are limited. Recently, we defined 6-sulfo LacNAc (slan) DCs as a major subpopulation of myeloid human blood DCs, which represent principal producers of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin (IL)-12. Functional data revealed that slanDCs efficiently induce neoantigen-specific CD4+ T cells and activate tumor-reactive cytotoxic T cells. When evaluating the crosstalk between slanDCs and NK cells in this study, we found that lipopolysaccharide (LPS)-activated slanDCs efficiently enhance NK cell CD69 expression and interferon (IFN)-gamma secretion. NK cell-mediated tumor-directed cytotoxicity was significantly improved by slanDCs. NK cell activation induced by slanDCs was critically dependent on IL-12. When investigating the impact of NK cells on the immunostimulatory capacity of slanDCs, we observed that they promote DC maturation. In addition, NK cells strongly enhanced the secretion of immunomodulatory IL-12 and reduced the release of immunosuppressive IL-10 by slanDCs. IFN-gamma and cell-to-cell contact contributed to these effects. Furthermore, data revealed that DC-NK cell crosstalk improves slanDC-mediated differentiation of naïve CD4+ T lymphocytes into IFN-gamma-producing Th1 cells. In conclusion, we demonstrate a reciprocal activating interaction between slanDCs and NK cells, which may play a pivotal role in the regulation of antitumor immunity.

Clinical significance of MHC class II-associated invariant chain expression in human gastric carcinoma

MHC class II antigens serve as restricted elements for cell presenting antigens to CD4+ helper T cells. CD4+ T cells and CD8+ cytotoxic T cells, which are tumor-infiltrating lymphocytes (TILs), and play a major role in the survey and attack against tumor cells in primary lesions. Invariant chain (Ii) has several functions in MHC class II-restricted antigen presentation. In addition, Ii is found to be closely involved in the regulation of anti-tumor immunity in several tumor types. However, the significance of Ii expression in tumor cells is not fully illustrated. Immunohistochemical staining of Ii expression was performed in 58 cases of human gastric carcinoma specimens. The prognostic analysis of patients with gastric carcinoma was also performed. A total of 67.2% (39/58) gastric carcinomas were found to be Ii-positive, whereas only 20.7% (12/58) showed positive immunoreactivity with anti-MHC class II determinants. Furthermore, Ii expression showed significant correlation with the differentiation of gastric carcinoma (p<0.05). Ii expression also showed an inverse correlation with the frequency of TILs around carcinoma tissues, as well as with the prognosis of gastric carcinoma (p<0.01). Ii expression is closely correlated with anti-tumor immunity in human gastric carcinoma. Therefore, Ii may serve as an independent clinical marker for poor biological behavior and prognostic analysis in patients with gastric carcinoma.