A Global Approach to Tumor Immunology

Biological and clinical advances in the understanding of tumor immunology suggest that immune responsiveness of human tumors is a complex biological phenomenon that could be best studied by a real-time comparison of tumor/host interactions in the tumor microenvironment through a high-throughput discovery-driven approach.This conclusion is derived from our recognition that too many hypotheses or,in other words,no solid single hypothesis exist,based on experimental results,to further drive experimentation in human subjects.Functional genomic studies entertained during the last few years consolidated the belief that in humans the interactions between tumor and immune cells are too complex to be approached exclusively with a hypothesis driven method.We believe that immune cells suit cancer cells in a Yin and Yang balance by opposing and yet mutually depending on each other.Indeed,immune infiltration in tumors may play a dual role modulating in different circumstances cancer cell growth or destruction through a physiological modulation of inflammation.It is reasonable to question what induces inflammation at the tumor site.We hypothesize that inflammation is primarily driven by the phenotype of tumor cells that can modulate their microenvironment through cell-to-cell interactions or the secretion of soluble factors.Thus,in analogy the observation of immune cells within tumors parallels the presence of paramedics,police and firemen at the scene of an accident,which is reactive to and not causative of the occurrence.In this review we will explore this hypothesis by reporting and summarizing most of our recent work in the frame of available literature on the subject.Cellular & Molecular Immunology.2004;1(4):256-265.

Core fucosylation and its roles in gastrointestinal glycoimmunology

Glycosylation is a common post-translational modification in eukaryotic cells.It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function.Core fucosylation plays a vital role in the immune response.Most immune system molecules are core fucosylated glycoproteins such as complements,cluster differentiation antigens,immunoglobulins,cytokines,major histocompatibility complex molecules,adhesion molecules,and immune molecule synthesis-related transcription factors.These core fucosylated glycoproteins play important roles in antigen recognition and clearance,cell adhesion,lymphocyte activation,apoptosis,signal transduction,and endocytosis.Core fucosylation is dominated by fucosyltransferase 8(Fut8),which catalyzes the addition ofα-1,6-fucose to the innermost GlcNAc residue of N-glycans.Fut8 is involved in humoral,cellular,and mucosal immunity.Tumor immunology is associated with aberrant core fucosylation.Here,we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.

N^(6)-methyladenosine(m^(6)A)RNA modification in tumor immunity

Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition.N^(6)-methyladenosine(m^(6)A)modification,the most prevalent epigenetic modification of mammalian mRNAs,has essential functions in regulating the processing and metabolism of its targeted RNAs,and therefore affects various biological processes including tumorigenesis and progression.Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m^(6)A modification in the regulation of tumor immunity.In this review,we summarize recent research progress in the potential roles of m^(6)A modification in tumor immunoregulation,with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways.Furthermore,we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape,and we discuss the prognostic value and therapeutic efficacy of m^(6)A regulators in a variety of cancer types.

Nanomedicine-based drug delivery towards tumor biological and immunological microenvironment

The complex tumor microenvironment is a most important factor in cancer development.The biological microenvironment is composed of a variety of barriers including the extracellular matrix and associated cells such as endothelia cells,pericytes,and cancer-associated fibroblasts.Different strategies can be utilized to enhance nanoparticle-based drug delivery and distribution into tumor tissues addressing the extracellular matrix or cellular components.In addition to the biological microenvironment,the immunological conditions around the tumor tissue can be very complicated and cancer cells have various ways of evading immune surveillance.Nanoparticle drug delivery systems can enhance cancer immunotherapy by tuning the immunological response and memory of various immune cells such as T cells,B cells,macrophages,and dendritic cells.In this review,the main components in the tumor biological and immunological environment are discussed.The focus is on recent advances in nanoparticle-based drug delivery systems towards targets within the tumor microenvironment to improve cancer chemotherapy and immunotherapy.

Memory T cells: strategies for optimizing tumor immunotherapy

Several studies have demonstrated that memory T cells including stem cell memory (Tscm) T cells and central memory (Tcm) T cells show superior persistence and antitumor immunity compared with effector memory T (Tem) cells and effector T (Teff) cells.Furthermore,the Tcm/Teff ratio has been reported to be a predictive biomarker of immune responses against some tumors.Thus,a system-level understanding of the mechanisms underlying the differentiation of effector and memory T cells is of increasing importance for developing immunological strategies against various tumors.This review focuses on recent advances in efficacy against tumors,the origin,formation mechanisms of memory T cells,and the role of the gut microbiota in memory T cell formation.Furthermore,we summarize strategies to generate memory T cells in (ex) vivo that,might be applicable in clinical practice.

The breast tumor microenvironment alters the phenotype and function of natural killer cells

Natural killer （NK） ceils are innate immune cells with the ability to identify and eliminate transformed cells. However, within tumors, many studies have described NK cells as non-functional. The developmental stage of tumor-associated NK cells and how this may relate to functionality has not been explored. We examined the developmental state of NK cells from polyoma middle T antigen （pyMT） transgenic mouse （MMTV-pMT） breast tumors. In pyMT tumors, NK cells were immature as evidenced by their decreased expression of DX5 and their CD27~~WCD1 lbI^w phenotype. These immature NK cells also had increased expression of NKG2A and expressed low levels of NKp46, perforin, and granzyme B. In contrast, splenic NK cells isolated from the same mice maintained their maturity and their expression of activation markers. To delineate whether the tumor microenvironment directly alters NK cells, we adoptively transferred labeled NK cells and followed their activation status in both the spleen and the tumor. NK cells that arrived at the tumor had half the expression of NKp46 within three days of transfer in comparison to those which arrived at the spleen. In an effort to modify the tumor microenvironment and assess the plasticity of intratumoral NK cells, we treated pyMT tumors with IL-12 and anti-TGF-β. After one week of treatment, the maturity of tumor-associated NK cells was increased; thus, indicating that these cells possess the ability to mature and become activated. A better understanding of how NK cells are modified by the tumor microenvironment will held to develop strategies aimed at bolstering immune resoonses against tumors.

Synthetic immunology:T-cell engineering and adoptive immunotherapy

During the past decades,the rapidly-evolving cancer is hard to be thoroughly eliminated even though the radiotherapy and chemotherapy do exhibit efficacy in some degree.However,a breakthrough appeared when the adoptive cancer therapy[1]was developed,especially T cells armed with chimeric antigen receptors(CARs)showed great potential in tumor clinical trials recently.CAR-T cells successfully elevated the efficiency and specificity of cytotoxicity.In this review,we will talk about the design of CAR and CAR-included combinatory therapeutic applications in the principles of systems and synthetic immunology.

Postoperative Regulatory T-Cells and Natural Killer Cells in Stage I Nonsmall Cell Lung Cancer Underwent Video-assisted Thoracoscopic Lobectomy or Thoracotomy

Background： Regulatory T-cells （Treg） play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer （NSCLC）. Video-assisted thoracoscopic （VATS） lobectomy, as a minimal invasive procedure for treating NSCLC, may have relatively less impact on the patient＇s immune system. This study aimed to observe perioperative dynamics of circulating Treg and natural killer （NK） cell levels in NSCLC patients who underwent major Iobectomy by VATS or thoracotomy. Methods： Totally, 98 consecutive patients with stage I NSCLC were recruited and assigned into VATS or thoracotomy groups. Peripheral blood samples were taken on 1-day prior to operation, postoperative days （PODs） I, 3, 7, 30, and 90. Circulating Treg and NK cell counts were assayed by flow cytometry, defined as CD4＋CD25＋CD127w cells in CD4＋ lymphocytes and CD56＋I6＋CD3 cells within CD45＋ leukocytes respectively. With SPSS software version 21.0 （SPSS Inc., USA）, differences between VATS and thoracotomy groups were determined by one-way analysis of variance （ANOVA）, and differences between preoperative baseline and PODs in each group were evaluated by one-way ANOVA Dunnett t-test. Results： In both groups, postoperative Treg percentages were lower than preoperative status. No statistical difference was found between VATS and thoracotomy groups on PODs 1, 3, 7, and 30. On POD 90, Treg percentage in VATS group was significantly lower than in thoracotomy group （5.26 ± 2.75 vs. 6.99 ±3.60, P = 0.012）. However, a higher level of NK was found on all PODs except on POD 90 in VATS group, comparing to thoracotomy group. Conclusions： Lower Treg level on POD 90 and higher NK levels on PODs 1, 3, 7, 30 in VATS group might imply better preserved cell-mediated immune function in NSCLC patients, than those in thoracotomy group.

Heterogeneity of aberrant immunoglobulin expression in cancer cells

Accumulating evidence has shown that immunoglobulin(Ig)is‘unexpectedly’expressed by epithelial cancer cells and that it can promote tumor growth.The main purpose of this study was to explore the components of the cancerous Ig and its possible function.The presence of cancerous Ig in the Golgi apparatus was confirmed by immunofluorescence,indirectly suggesting that the cancerous Ig was processed and packaged in cancer cells.Western blot analysis and ELISA results indicated that cancer cells produced membrane Ig and secreted Ig into the supernatant fraction.The cancerous Ig consists of an a heavy chain and a k light chain.Finally,by analyzing the Ig components pulled down by protein A beads,the cancerous Ig was found to be structurally distinct from normal Ig.The cancerous Ig was truncated or aberrant.Although the underlying mechanism that causes the abnormalities has not been determined,our current discoveries strengthen our previous findings and promise fruitful future explorations.

The role of myeloid-derived suppressor cells in gastrointestinal cancer

Gastrointestinal(GI)cancer encompasses a range ofmalignancies that originate in the digestive system,which together represent the most common form of cancer diagnosed worldwide.However,despite numerous advances in both diagnostics and treatment,the incidence and mortality rate of GI cancer are on the rise.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature myeloid cells that increase in number under certain pathological conditions,such as infection and inflammation,and this expansion is of particular relevance to cancer.MDSCs are heavily involved in the regulation of the immune system and act to dampen its response to tumors,favoring the escape of tumor cells from immunosurveillance and increasing both metastasis and recurrence.Several recent studies have supported the use of MDSCs as a prognostic and predictive biomarker in patientswith cancer,and potentially as a novel treatment target.In the present review,the mechanisms underlying the immunosuppressive functions of MDSCs are described,and recent researches concerning the involvement of MDSCs in the progression,prognosis,and therapies of GI cancer are reviewed.The aim of this work was to present the development of novel treatments targeting MDSCs in GI cancer in the hope of improving outcomes for patients with this condition.