Qizhu anticancer prescription enhances immunosurveillance of liver cancer cells by regulating p21-dependent secretory phenotypes.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, largely due to the limitations of available therapeutic strategies. The traditional Chinese medicine Qizhu Anticancer Prescription (QZACP) can improve the quality of life and prolong the survival time of patients with HCC. However, the precise mechanisms underlying the anti-cancer properties of QZACP remain unclear. PURPOSE: This study examined the anti-hepatocarcinogenic properties of QZACP, with a specific focus on its influence on the p21-activated secretory phenotype (PASP)-mediated immune surveillance, to elucidate the underlying molecular pathways involved in HCC. MATERIALS AND METHODS: Cell proliferation was measured using the Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, and clonogenic assays. The cell cycle was evaluated using flow cytometry, and senescence was identified by staining with senescence-associated beta-galactosidase (SA-ß-gal). A primary liver cancer model produced by diethylnitrosamine was established in C57 BL/6 mice to assess the tumor-inhibitory effect of QZACP. The liver's pathological characteristics were examined using hematoxylin and eosin staining. PASP screening was performed using GeneCards, DisGeNet, Online Mendelian Inheritance in Man, and The Cancer Genome Atlas databases. Western blot analysis, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and Transwell migration assays were performed. RESULTS: Serum containing QZACP enhanced p21 expression, triggered cell cycle arrest, accelerated cell senescence, and suppressed cell proliferation in Huh7 and MHCC-97H liver cancer cells. QZACP reduced the quantity and dimensions of liver tumor nodules and enhanced p21 protein expression, SA-ß-Gal staining in tumor lesions, and cytotoxic CD8+ T cell infiltration. Bioinformatic analyses indicated that PASP factors, including hepatocyte growth factor, decorin (DCN), dermatopontin, C-X-C motif chemokine ligand 14 (CXCL14), and Wnt family member 2 (WNT2), play an important role in the development of HCC. In addition, these factors are associated with the presence of natural killer cells and CD8+ T cells within tumors. Western blotting and ELISA confirmed that QZACP increased DCN, CXCL14, and WNT2 levels in tumor tissues and peripheral blood. CONCLUSIONS: QZACP's suppression of HCC progression may involve cell senescence mediated via p21 upregulation, DCN, CXCL14, and WNT2 secretion, and reversal of the immunosuppressive microenvironment. This study provides insights that can be used in the development of new treatment strategies for HCC.

Urolithin-A Promotes CD8+ T Cell-mediated Cancer Immunosurveillance via FOXO1 Activation.

Naïve T cells are key players in cancer immunosurveillance, even though their function declines during tumor progression. Thus, interventions capable of sustaining the quality and function of naïve T cells are needed to improve cancer immunoprevention.In this context, we studied the capacity of Urolithin-A (UroA), a potent mitophagy inducer, to enhance T cell-mediated cancer immunosurveillance.We discovered that UroA improved the cancer immune response by activating the transcription factor FOXO1 in CD8+ T cell. Sustained FOXO1 activation promoted the expression of the adhesion molecule L-selectin (CD62L) resulting in the expansion of the naïve T cells population. We found that UroA reduces FOXO1 phosphorylation favoring its nuclear localization and transcriptional activity. Overall, our findings determine FOXO1 as a novel molecular target of UroA in CD8+ T cells and indicate UroA as promising immunomodulator to improve cancer immunosurveillance. SIGNIFICANCE: Urolithin-A, a potent mitophagy inducer, emerges as a promising tool to enhance cancer immunosurveillance by activating the FOXO1 transcription factor in CD8+ T cells. This activation promotes the expansion of naïve T cells, offering a novel avenue for improving cancer immune response and highlighting UroA as a potential immunomodulator for bolstering our body's defenses against cancer.

IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer.

BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS: In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS: These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.

Synergistic Tumor Cytolysis by NK Cells in Combination With a Pan-HDAC Inhibitor, Panobinostat.

Histone deacetylases (HDAC) are frequently overexpressed in tumors, and their inhibition has shown promising anti-tumor effects. However, the synergistic effects of HDAC inhibition with immune cell therapy have not been fully explored. Natural killer (NK) cells are cytotoxic lymphocytes for anti-tumor immune surveillance, with immunotherapy potential. We showed that a pan-HDAC inhibitor, panobinostat, alone demonstrated anti-tumor and anti-proliferative activities on all tested tumors in vitro. Additionally, panobinostat co-treatment or pretreatment synergized with NK cells to mediate tumor cell cytolysis. Mechanistically, panobinostat treatment increased the expression of cell adhesion and tight junction-related genes, promoted conjugation formation between NK and tumor cells, and modulates NK cell-activating receptors and ligands on tumor cells, contributing to the increased tumor cytolysis. Finally, panobinostat therapy led to better tumor control and synergized with anti-PD-L1 therapy. Our data highlights the anti-tumor potential of HDAC inhibition through tumor-intrinsic toxicity and enhancement of NK -based immunotherapy.

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

Prospects and Challenges for T Cell-Based Therapies of HCC.

The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.

Control of Macrophage Inflammation by P2Y Purinergic Receptors.

Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.

Treatment-free remission and immunity in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is caused by the reciprocal translocation t(9;22)(q34;q11), resulting in the BCR-ABL1 fusion gene. BCR-ABL1 tyrosine kinase inhibitors (TKIs) improve overall survival in patients with chronic phase CML (CML-CP). Approximately half of the patients who achieve a durable deep molecular response can achieve sustained treatment-free remission (TFR) after TKI discontinuation; thus TFR is now a therapeutic goal for most patients with CML-CP. Sensitive BCL-ABL1 transcript detection methods reveal that evidence of residual CML cells remains in patients who achieve sustained TFR, indicating that the host immune system protects against CML relapse. The human immune system is composed of innate and adaptive arms. Natural killer cells are major components of the innate immune system, while T cells are major components of the adaptive immune system. Myeloid-derived suppressor cells and regulatory T cells, both suppressors of the immune response, have important roles in the regulation of CML. Here, we review the current understanding of the immune response in CML, especially in TFR.

Exercise Benefits Meet Cancer Immunosurveillance: Implications for Immunotherapy.

Regular exercise reduces the risk of cancer. One potential mechanism for this efficacy is improved antitumor immunity. This is an important issue because evading immune destruction is a hallmark of cancer and immunotherapy is reshaping cancer treatment. Here we review recent developments reported by Wennerberg et al., Garritson et al., Martín-Ruiz et al., and Rundqvist et al. on the effects of exercise on anticancer immune cell effectors.

STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.

Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1ß isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1α/α) or the STAT1ß (Stat1ß/ß ) isoform. NK cells from Stat1α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1ß/ß mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1-/- ). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1ß/ß mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1ß/ß mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.

Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1.

BACKGROUND: Immune checkpoint blockade (ICB) therapy has demonstrated considerable clinical benefit in several malignancies, but has shown favorable response in only a small proportion of cancer patients. Recent studies have shown that matrix metalloproteinases (MMPs) are highly associated with the microenvironment of tumors and immune cells. However, it is unknown whether MMPs are involved in immunotherapy. METHODS: Here, we used integrative analysis to explore the expression landscape of the MMP family and its association with immune features across multiple cancer types. We used T cell cytotoxicity-mediated tumor killing assay to determine the co-cultured T cell activity of SB-3CT, an MMP2/9 inhibitor. We then used in vitro assays to examine the regulating roles of SB-3CT on PD-L1. We further characterized the efficacy of SB-3CT, in combination with anti-PD-1 and/or anti-CTLA4 treatment in mouse models with melanoma and lung cancer. RESULTS: Our computational analysis demonstrated a strong association between MMP2/9 and immune features. We demonstrated that inhibition of MMP2/9 by SB-3CT significantly reduced the tumor burden and improved survival time by promoting anti-tumor immunity. Mechanistically, we showed that SB-3CT treatment significantly diminished both mRNA and protein levels of PD-L1 in cancer cells. Pre-clinically, SB-3CT treatment enhanced the therapeutic efficacy of PD-1 or CTLA-4 blockade in the treatment of both primary and metastatic tumors. CONCLUSIONS: Our study unraveled novel molecular mechanisms regarding the regulation of tumor PD-L1 and provided a novel combination therapeutic strategy of SB-3CT and ICB therapy to enhance the efficacy of immunotherapy.

Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells.

Acute lymphoblastic leukaemia (ALL) is the most frequent childhood cancer and, although it is highly treatable, resistance to therapy, toxicity and side effects remain challenging. The synthetic glucocorticoid (GC) dexamethasone (Dex) is commonly used to treat ALL, the main drawback of which is the development of resistance to this treatment. The aim of the present study was to investigate potential molecular circuits mediating resistance and sensitivity to GC­induced apoptosis in ALL. The leukaemia cell lines CEM­C7­14, CEM­C1­15 and MOLT4 treated with chloroquine (CLQ), thapsigargin (TG) and rotenone (ROT) were used to explore the roles of autophagy, endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and reactive oxygen species (ROS) generation in the response to GC treatment. ROS levels were associated with increased cell death and mitochondrial membrane potential in rotenone­treated CEM cells. Autophagy inhibition by CLQ exhibited the strongest cytotoxic effect in GC­resistant leukaemia. Autophagy may act as a pro­survival mechanism in GC­resistant leukaemia since increasing trends in beclin­1 and microtubule­associated protein 1 light chain 3α levels were detected in CEM­C1­15 and MOLT4 cells treated with Dex, whereas decreasing trends in these autophagy markers were observed in CEM­C7­14 cells. The intracellular protein levels of the ER stress markers glucose­regulated protein (GRP)78 and GRP94 were stimulated by Dex only in the GC­sensitive cells, suggesting a role of these chaperones in the GC­mediated ALL cell death. Increased cell surface levels of GRP94 were recorded in CEM­C7­14 cells treated with combination of Dex with TG compared with those in cells treated with TG alone, whereas decreasing trends were observed in CEM­C1­15 cells under these conditions. Taken together, the results of the present study demonstrated that autophagy may be a pro­survival mechanism in GC­resistant leukaemia, and by modulating intracellular and surface GRP94 protein levels, Dex is involved in the regulation of ER stress/UPR­dependent cell death and immune surveillance. These observations may be of clinical importance if confirmed in patients.

Effects of PD-1/PD-L1 signaling pathway on intestinal flora in patients with colorectal cancer.

OBJECTIVE: To explore the effects of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway on the intestinal flora in patients with colorectal cancer (CRC). METHODS: A total of 30 CRC patients treated with PD-1 monoclonal antibody therapy in the Oncology Department of our hospital from January 2018 to January 2019, and another 30 patients treated with routine non-immune therapy were enrolled. The feces specimens were collected for sequencing, the CRC model was established, and the 16S rRNA gene sequences in intestinal flora in feces specimens of mice were analyzed. RESULTS: The 3-month progression-free survival could not be predicted through the gene count or abundance of metagenomic species (MGS) in intestinal microflora of patients. The gene count or MGS abundance was related to the clinical progression-free response. There were abundant unclassified Escherichia coli, s_lactobacillus and s_unclassified parasutterella in patients treated with PD-1. The reflection curve of microbiota had an obvious difference in richness (Chao1), but had no apparent difference in diversity (Shannon). CONCLUSION: The PD-1/PD-L1 signaling pathway can regulate the metabolic activity of intestinal flora, thereby promoting immune surveillance of tumors.

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.

Artemisinin sensitizes tumor cells to NK cell-mediated cytolysis.

The antimalarial drug Artemisinin has been reported to possess direct anti-tumor effects on various types of tumor cells. However, its anti-tumor potential has not been fully revealed, and its effects on tumor susceptibility to immune surveillance by the host are still unknown. Natural killer (NK) cells are the first line in tumor surveillance by the host, and have been recognized as a promising target for tumor immunotherapy. Here, we reported that Artemisinin sensitized tumor cells to NK cell cytolysis. Both human K562 and Raji tumor cells, and mouse YAC-1 tumor cells were more susceptible to human or mouse NK cell cytolysis in vitro after Artemisinin pretreatment. Conjugation formation between tumor cells and NK cells was increased after pretreatment with Artemisinin. Such effects on tumor cells by Artemisinin might not be the results of tumor recognition by NK cells, since major ligands of NK cell surface receptors were not affected. Mechanistically, although Artemisinin didn't induce tumor cell apoptosis, Artemisinin enriched apoptosis-related gene sets in these tumor cells, which might predispose tumor cells to apoptosis upon NK cell cytolysis. Moreover, NK cell numbers, percentages, maturation and functions were preserved in the presence of Artemisinin in vitro, suggesting that Artemisinin displays detrimental effects only on tumor cells but not on immune cells. These data reveal a novel anti-tumor mechanism of Artemisinin and demonstrate that Artemisinin could be a promising drug candidate for cancer treatment.

Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging.

Cellular senescence is a tumor suppressive mechanism that can paradoxically contribute to aging pathologies. Despite evidence of immune clearance in mouse models, it is not known how senescent cells (SnCs) persist and accumulate with age or in tumors in individuals. Here, we identify cooperative mechanisms that orchestrate the immunoevasion and persistence of normal and cancer human SnCs through extracellular targeting of natural killer receptor signaling. Damaged SnCs avoid immune recognition through MMPs-dependent shedding of NKG2D-ligands reinforced via paracrine suppression of NKG2D receptor-mediated immunosurveillance. These coordinated immunoediting processes are evident in residual, drug-resistant tumors from cohorts of >700 prostate and breast cancer patients treated with senescence-inducing genotoxic chemotherapies. Unlike in mice, these reversible senescence-subversion mechanisms are independent of p53/p16 and exacerbated in oncogenic RAS-induced senescence. Critically, the p16INK4A tumor suppressor can disengage the senescence growth arrest from the damage-associated immune senescence program, which is manifest in benign nevi lesions where indolent SnCs accumulate over time and preserve a non-pro-inflammatory tissue microenvironment maintaining NKG2D-mediated immunosurveillance. Our study shows how subpopulations of SnCs elude immunosurveillance, and reveals secretome-targeted therapeutic strategies to selectively eliminate -and restore the clearance of- the detrimental SnCs that actively persist after chemotherapy and accumulate at sites of aging pathologies.

OMIC signatures to understand cancer immunosurveillance and immunoediting: Melanoma and immune cells interplay in immunotherapy.

Melanoma is the deadliest form of skin cancer. Cutaneous melanomas usually originate from exposure to the mutagenic effects of ultraviolet radiation, and as such they exhibit the highest rate of somatic mutations than any other human cancer, and an extensive expression of neoantigens concurrently with a dense infiltrate of immune cells. The coexistence of high immunogenicity and high immune cell infiltration may sound contradictory for cancers carrying a gloomy outcome. However, recent studies have unveiled a variety of immunosuppressive mechanisms that often permeate the tumor microenvironment and that are responsible for tumor escaping from immunosurveillance mechanisms. Nonetheless, this particular immune profile has opened a new window of treatments based on immunotherapy that have significantly improved the clinical outcome of melanoma patients. Still, positive and complete therapy responses have been limited, and this particular cancer continues to be a major clinical challenge. The transcriptomic signatures of those patients with clinical benefit and those with progressive disease have provided a more complete picture of the universe of interactions between the tumor and the immune system. In this review, we integrate the results of the immunotherapy clinical trials to discuss a novel understanding of the mechanisms guiding cancer immunosurveillance and immunoediting. A clear notion of the cellular and molecular processes shaping how the immune system and the tumor are continuously coevolving would result in the rational design of combinatory therapies aiming to counteract the signaling pathways and cellular processes responsible for immunoescape mechanisms and provide clinical benefit to immunotherapy nonresponsive patients.

Therapeutic Targeting of HIV Reservoirs: How to Give T Cells a New Direction.

HIV cannot be cured by current antiretroviral therapy (ART) because it persists in a transcriptionally silent form in long-lived CD4+ cells. Leading efforts to develop a functional cure have prioritized latency reversal to expose infected cells to immune surveillance, coupled with enhancement of the natural cytolytic function of immune effectors, or "kick and kill." The most clinically advanced approach to improving the kill is therapeutic immunization, which aims to augment or re-focus HIV-specific cytolytic T cell responses. However, no vaccine strategy has enabled sustained virological control after ART withdrawal. Novel approaches are needed to overcome the limitations of natural adaptive immune responses, which relate to their specificity, potency, durability, and access to tissue reservoirs. Adoptive T cell therapy to treat HIV infection was first attempted over two decades ago, without success. Since then, progress in the field of cancer immunotherapy, together with recognition of the similarities in tumor microenvironments and HIV reservoirs has reignited interest in the application of T cell therapies to HIV eradication. Advances in engineering of chimeric antigen receptor (CAR)-transduced T cells have led to improved potency, persistence and latterly, resistance to HIV infection. Immune retargeting platforms have incorporated non-neutralizing and broadly neutralizing antibodies to generate Bispecific T cell Engagers (BiTEs) and Dual-Affinity Re-Targeting proteins (DARTs). T cell receptor engineering has enabled the development of the first bispecific Immune-mobilizing monoclonal T Cell receptors Against Viruses (ImmTAV) molecules. Here, we review the potential for these agents to provide a better "kill" and the challenges ahead for clinical development.

Complement as a Biological Tool to Control Tumor Growth.

Deposits of complement components have been documented in several human tumors suggesting a potential involvement of the complement system in tumor immune surveillance. In vitro and in vivo studies have revealed a double role played by this system in tumor progression. Complement activation in the cancer microenvironment has been shown to promote cancer growth through the release of the chemotactic peptide C5a recruiting myeloid suppressor cells. There is also evidence that tumor progression can be controlled by complement activated on the surface of cancer cells through one of the three pathways of complement activation. The aim of this review is to discuss the protective role of complement in cancer with special focus on the beneficial effect of complement-fixing antibodies that are efficient activators of the classical pathway and contribute to inhibit tumor expansion as a result of MAC-mediated cancer cell killing and complement-mediated inflammatory process. Cancer cells are heterogeneous in their susceptibility to complement-induced killing that generally depends on stable and relatively high expression of the antigen and the ability of therapeutic antibodies to activate complement. A new generation of monoclonal antibodies are being developed with structural modification leading to hexamer formation and enhanced complement activation. An important progress in cancer immunotherapy has been made with the generation of bispecific antibodies targeting tumor antigens and able to neutralize complement regulators overexpressed on cancer cells. A great effort is being devoted to implementing combined therapy of traditional approaches based on surgery, chemotherapy and radiotherapy and complement-fixing therapeutic antibodies. An effective control of tumor growth by complement is likely to be obtained on residual cancer cells following conventional therapy to reduce the tumor mass, prevent recurrences and avoid disabilities.