Immunosurveillance function of human mast cell?

Mast cell (MC) is so widely recognized as a critical effector in allergic disorders that it can be difficult to think of MC in any other context. Indeed, MCs are multifunctional and recently shown that MCs can also act as antigen presenters as well as effector elements of human immune system. First observations of their possible role as anti-tumor cells in peri- or intra-tumoral tissue were mentioned five decades ago and a high content of MCs is considered as a favorable prognosis,consistent with this study. Believers of this hypothesis assumed them to be inhibitors of tumor development through their pro-apoptotic and -necrolytic granules e.g.,granzymes and TNF-α. However, some still postulate them to be enhancers of tumor development through their effects on angiogenesis due to mostly tryptase.There are also some data suggesting increased MC density causes tumor development and indicates bad prognosis. Furthermore, since MC-associated mediators have shown to influence various aspects of tumor biology, the net effect of MCs on the development/progression of tumors has been difficult to evaluate. For instance, chymase induces apoptosis in targets; yet,tryptase, another MC protease, is a well-known mitogen.MCs with these various enzyme expression patterns may mediate different functions and the predominant MC type in tissues may be determined by the environmental needs. The coexistence of tryptase-expressing MCs(MCT) and chymase and tryptase-expressing MCs (MCTC)in physiological conditions reflects a naturally occurring balance that contributes to tissue homeostasis. We have recently discussed the role and relevance of MC serine proteases in different bone marrow diseases.

Roles of a metastasis-associated molecule, RTVP-1, in cancer immunosurveillance

Objective: To elucidate distinct functions of a recently identified cancer metastasis-associated molecule, related to testes-specific, vespid, and pathogenesis protein-1 (RTVP-1) in the mammalian immune system. Methods: Immunohistochemical assays and functional analysis on the immune system were performed on RTVP-/- mice and RTVP-1+/+ mice. Protein-protein interaction (PPI) was used to predict the functions of RTVP-1. Results: Abnormal lymphocyte growth kinetics and reduced numbers of CD8+ T cells were revealed in lymph nodes of RTVP-1-/- mice. Expression of phenotypic markers of maturation in bone marrow-derived dendritic cells (DC) was impaired in RTVP-1-/- DC following antigenic stimulation in vitro and RTVP-1-/- DC failed to provide normal CD4+ T cell stimulatory activities in vivo. RTVP-1-/- mice failed to generate normal CTL or antibody responses in vivo after vaccination. In vivo tumor challenge experiments using a mouse cancer cell line demonstrated that the growth rate of subcutaneous tumors in RTVP-1-/- mice was significantly increased and CD8+ T cell infiltration significantly reduced compared to RTVP-1+/+ mice. PPI showed that RTVP-1 protein closely interacted with molecules associated with immune response and cancer metastasis. Conclusion: RTVP-1 might function as a tumor metastasis suppressor and immunosurveillance molecule in cancer.

NK cells play a significant role in immunosurveillance at the early stage of MLL-AF9 acute myeloid leukemia via CD226/CD155 interactions

Acute myeloid leukemia(AML) is an aggressive hematological malignancy, and the mechanism underlying immune system involvement in leukemia development is unclear. In the present study, we utilized a myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3(MLLT3/MLL-AF9)-induced AML mouse model with or without exposure to irradiation. We found that the leukemia cells could survive and expand in hosts with intact immune systems, whereas leukemia progression was accelerated in mice with impaired immune systems. Moreover, the leukemia cells escaped from host immunosurveillance via editing their immunogenicity, including the up-regulation of an inhibitory antigen(i.e., CD47) and the down-regulation of active antigens(i.e., CD86, CD54, retinoic acid early transcript(RAE), histocompatibility 2, D region locus b(H2-Db) and H2-Dd). Natural killer(NK) cells were activated in the early phase of AML progression, whereas T cells were stimulated in the late phase. Furthermore, NK cell depletion showed that NK cells were necessary for the elimination of leukemia cells in our AML mouse model. Notably, CD155/CD226 primarily mediated the interaction between NK cells and leukemia cells and contributed to the antitumor effects of NK cells during the early phase of AML. Clinical data from patients with diverse hematological malignancies showed that CD155 expression was decreased in hematological malignancies. Taken together, our results demonstrate that NK cells play a pivotal role in immunosurveillance against leukemia cells during the early stage of AML primarily through the CD226/CD155 interaction; however, NK cells are not sufficient to eliminate leukemia cells.

Intestinal inflammation and colorectal cancer:A doubleedged sword?

Chronic inflammation is thought to be the leading cause of many human cancers including colorectal cancer(CRC).Accordingly,epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease,the two major forms of inflammatory bowel disease,have an increased risk of developing CRC.In recent years,the role of immune cells and their products have been shown to be pivotal in initiation and progression of colitis-associated CRC.On the other hand,activation of the immune system has been shown to cause dysplastic cell elimination and cancer suppression in other settings.Clinical and experimental data herein reviewed,while confirming chronic inflammation as a risk factor for colon carcinogenesis,do not completely rule out the possibility that under certain conditions the chronic activation of the mucosal immune system might protect from colonic dysplasia.

Arsenic trioxide elicits prophylactic and therapeutic immune responses against solid tumors by inducing necroptosis and ferroptosis

Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8^(+) T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.

Double-edged roles of IFNγ in tumor elimination and immune escape

Interferon-gamma (IFNγ) is a pleiotropic cytokine implicated in tumor immune surveillance, with its antiproliferative, pro-apoptotic, and immune-provoking effects. Regarding the antitumor effects of IFNγ, IFNγ-dependent therapies have been proposed and have undergone many clinical trials for various cancer types but the outcomes were not satisfactory. Recent studies have suggested that cancer cells develop immune evasion strategies to escape from IFNγ-dependent immunosurveillance by various mechanisms. In this review, we summarize recent advances in the effects and molecular mechanisms of IFNγ on target cells, as well as potential immune escape mechanisms of tumor cells. Furthermore, we discuss how to target IFNγ signaling and overcome immune evasion to provide promising therapeutic strategies for the treatment of patients with cancer.

Immunogenic effects of chemotherapyinduced tumor cell death

Emerging evidence suggests that the clinical success of conventional chemotherapy is not solely attributed to tumor cell toxicity,but also results from the restoration of immunosurveillance,which has been largely neglected in the past preclinical and clinical research.Antitumor immune response can be primed by immunogenic cell death(ICD),a type of cell death characterized by cell-surface translocation of calreticulin(CRT),extracellular release of ATP and high mobility group box 1(HMGB1),and stimulation of type I interferon(IFN)responses.Here we summarize recent studies showing conventional chemotherapeutics as ICD inducers,which are capable of modulating tumor infiltrating lymphocytes(TILs)and reactivating antitumor immunity within an immuno-suppressive microenvironment.Such immunological effects of conventional chemotherapy are likely critical for better prognosis of cancer patients.Furthermore,combination of ICD-inducing chemotherapeutics with immunotherapy is a promising approach for improving the clinical outcomes of cancer patients.

The impact of the TIM gene family on tumor immunity and i mmunosuppression

Tumor immunoevasion is an advanced phase of cancer immunosurveillance in which tumor cells acquire the ability to circumvent host immune systems and exploit protumorigenic inflammation. T-cell immunoglobulin mucin （TIM） gene family members have emerged as critical checkpoint proteins that regulate multiple immune response phases and maintain immune homeostasis. Accumulating evidence demonstrates that tumor cells exploit TIM gene family members to evade immunosurveillance, whereas TIM gene family members facilitate the prevention of inflammation-related tumor progression. Thus, a comprehensive analysis to clarify the relative contributions of TIM gene family members in tumor progression may elucidate immunosurveillance systems in cancer patients.

An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T(CAR-T) cells

Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune-cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines(mainly interleukin 6 and C-reactive protein) were identified in two patients(Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.