Antitumor Activity Of Lymphocytes Research Articles

Immune Checkpoint-Modulating Photosensitizer That Targets BRD4 for Cancer Photoimmunotherapy.

Photodynamic therapy is an efficient approach to promote cytotoxic T lymphocyte tumor infiltration to convert immunologically cold tumors into hot tumors through the induction of immunogenic cell death . However, tumors usually overexpress immune checkpoints such as PD-L1 to suppress T lymphocyte antitumor activity and evade immune surveillance. Therefore, the design of efficient photosensitizers to overcome checkpoint-mediated immune evasion is highly necessary. In this work, we report the design of BRD-PS, a BRD4-targeting photosensitizer, as a new class of immunomodulatory photosensitizer termed an immune checkpoint-modulating photosensitizer, to solve this issue. On one hand, BRD-PS induces immunogenic pyroptosis and ferroptosis to promote the activation and tumor infiltration of cytotoxic T cells. On the other hand, BRD-PS suppresses the expression of PD-L1 to avoid immune evasion. This work demonstrated the feasibility of utilizing a single photosensitizer to simultaneously induce immunogenic cell death and PD-L1 downregulation for synergistic cancer photoimmunotherapy.

Targeting Potential of Innate Lymphoid Cells in Melanoma and Other Cancers.

Reinvigorating the killing function of tumor-infiltrating immune cells through the targeting of regulatory molecules expressed on lymphocytes has markedly improved the prognosis of cancer patients, particularly in melanoma. While initially thought to solely strengthen adaptive T lymphocyte anti-tumor activity, recent investigations suggest that other immune cell subsets, particularly tissue-resident innate lymphoid cells (ILCs), may benefit from immunotherapy treatment. Here, we describe the recent findings showing immune checkpoint expression on tissue-resident and tumor-infiltrating ILCs and how their effector function is modulated by checkpoint blockade-based therapies in cancer. We discuss the therapeutic potential of ILCs beyond the classical PD-1 and CTLA-4 regulatory molecules, exploring other possibilities to manipulate ILC effector function to further impede tumor growth and quench disease progression.

TIMELESS upregulates PD-L1 expression and exerts an immunosuppressive role in breast cancer

BackgroundUpregulation of the PD-L1 (CD274) immune checkpoint ligand on the tumor surface facilitates tumor immune escape and limits the application of immunotherapy in various cancers, including breast cancer. However, the mechanisms underlying high PD-L1 levels in cancers are still poorly understood.MethodsBioinformatics analyses and in vivo and in vitro experiments were carried out to assess the association between CD8+ T lymphocytes and TIMELESS (TIM) expression, and to discover the mechanisms of TIM, the transcription factor c-Myc, and PD-L1 in breast cancer cell lines.ResultsThe circadian gene TIM enhanced PD-L1 transcription and facilitated the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Bioinformatic analyses of our RNA sequencing data in TIM-knockdown breast cancer cells and public transcriptomic datasets showed that TIM might play an immunosuppressive role in breast cancer. We found that TIM expression was inversely associated with CD8+ T lymphocyte infiltration in human breast cancer samples and subcutaneous tumor tissues. In vivo and in vitro experiments demonstrated that TIM knockdown increased CD8+ T lymphocyte antitumor activity. Furthermore, our results showed that TIM interacts with c-Myc to enhance the transcriptional capability of PD-L1 and facilitates the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Moreover, public database analysis suggested that high TIM levels were positively related to PD-L1 inhibitor therapeutic response.ConclusionsMechanistically, we first found that TIM could upregulate PD-L1 by interacting with c-Myc to enhance the transcriptional capability of c-Myc to PD-L1. Altogether, our findings not only provide a novel therapeutic strategy to treat breast cancer by targeting the oncogenic effect of TIM but also indicate that TIM is a promising biomarker for predicting the benefit of anti-PD-L1 immunotherapy.

Fibroblasts Impair Migration and Antitumor Activity of NK-92 Lymphocytes in a Melanoma-on-Chip Model.

Adoptive cell therapy in solid tumors, such as melanoma, is impaired, but little is known about the role that the fibroblasts present in the tumor microenvironment could exert. However, the mechanism at play is not well understood, partly due to the lack of relevant pre-clinical models. Three-dimensional culture and microfluidic chips are used to recapitulate the dynamic interactions among different types of cells in the tumor microenvironment in controlled and physiological settings. In this brief report, we propose a reductionist melanoma-on-a-chip model for evaluating the essential role of fibroblasts in the antitumor activity of lymphocytes. To this end, 3D melanoma spheroids were monocultured and co-cultured with human dermal fibroblasts and the NK-92 cell migration towards the tumor compartment was tested in a commercially available microfluidic device. Utilizing confocal microscopy, we observed the different recruitment of NK-92 cells in the presence and absence of fibroblasts. Our results show that fibroblasts' presence inhibits immune effector recruiting by exploiting a 3D pre-clinical tumor model.

MiR-155 expression in antitumor immunity: The higher the better?

MicroRNAs are small noncoding RNAs that modulate gene expression either directly, by impairing the stability and/or translation of transcripts that contain their specific target sequence, or indirectly through the targeting of transcripts that encode transcription factors, factors implicated in signal transduction pathways, or epigenetic regulators. Abnormal expression of micro-RNAs has been found in nearly all types of pathologies, including cancers. MiR-155 has been the first microRNA to be implicated in the regulation of the innate and adaptative immune responses, and its expression is either increased or decreased in a variety of liquid and solid malignancies. In this review, we examine the oncogenic and antitumor potentials of miR-155, with special emphasize on its dose-dependent effects. We describe the impact of miR-155 levels on antitumor activity of lymphocytes and myeloid cells. We discuss miR-155 dose-dependent effects in leukemias and analyze results showing that miR-155 intermediate levels tend to be detrimental, whereas high levels of miR-155 expression usually prove beneficial. We also examine the beneficial effects of high levels of miR-155 expression in solid tumors. We discuss the possible causal involvement of miR-155 in leukemias and dementia in individuals with Down's syndrome. We finally propose that increasing miR-155 levels in immune cells might increase the efficiency of newly developed cancer immunotherapies, due to miR-155 ability to target transcripts encoding immune checkpoints such as cytotoxic T lymphocyte antigen-4 or programmed death-ligand 1.

P3.07-011 Investigation of Autologous Tumor-Killing Effect of Effusion-Associated Lymphocytes in Malignant Pleural Effusion of Lung Cancer

Many lung cancer patients developed malignant pleural effusion during the course of the disease. Previous studies revealed that the effusion associated lymphocytes (EAL) were in dysfunctional state which appeared to be immunosuppressed and unable to kill tumor cells. This study will evaluate the combined effects of IL-2, IL-12, αCD3 antibody (ab), and PD-1 ab on antitumor activity of lymphocytes. The underlying mechanism and relevant immune biomarkers will also be investigated.

A novel anticancer agent, benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride, activates multiple immunologic mechanisms of an antitumor response.

e12024 Background: BP-C1 (a combination of a benzene polycarboxylic acids complex (BP-Cx-1) with cis-diamineplatinum in a very low concentration) was demonstrated to be safe and effective in the treatment of stage IV breast cancer. Methods: In order to investigate whether the immune system mediates some of the clinical activity of BP-C1, we conducted an in vitro study of the immune modulating properties of this compound. The study was done using peripheral blood mononuclear cells from healthy donors. Results: It was demonstrated that the production of a number of cytokines was significantly increased by BP-C1, first of all IL-1beta, TNF-alpha, GM-CSF, IFN-gamma, and IL-25. The carrier molecule, BP-Cx-1, alone also stimulated IL-6 production. Experiments with isolated cultures of monocytes and lymphocytes indicated that the primary targets for these reagents are monocytes. Activation of monocytes leads to two major effects: a) the production of cytokines that are able to increase the anti-tumor activity of lymphocytes, and b) the acquired ability of monocytes to inhibit tumor cell growth. In addition, direct effects on lymphocytes were also demonstrated, exemplified by the induction of IL-25 production. Conclusions: In conclusion, it was demonstrated that BP-C1 and the related compounds are able to activate multiple immunological mechanisms of anti-tumor response.

Leukocyte-reduced blood transfusions: perioperative indications, adverse effects, and cost analysis.

Leukocyte-reduced blood transfusions: perioperative indications, adverse effects, and cost analysis.

Preadministration of a T-suppressor factor enhances tumor immunity in DBA/2 mice.

Previously we have described the isolation and characterization of a T-suppressor factor (TsF) from a T cell hybridoma (A10F), which has a degree of specificity for the DBA/2 mastocytoma P815. Administration of A10F intravenously at the time of tumor cell injection resulted in an accelerated rate of tumor growth, decreased cytotoxic T lymphocyte antitumor activity, and reduced survival time. In the work reported here, we have shown that administration of affinity-enriched A10F 7-14 days prior to tumor cell injection causes what appear to be reverse effects, in that an enhanced resistance to the P815 tumor is observed in vivo, an effect which we can correlate with the demonstration of antitumor cytotoxic T lymphocyte activity in vitro. These effects are dose-dependent since only doses of TsF at 20 micrograms or greater are effective. A similar effect was found when A10F was administered to DBA/2 mice 10 days prior to challenge with two unrelated tumors (L1210 and M-1). However, when another TsF (Fd11F) with apparent specificity for a nominal antigen was tested in this system, it had no effect on tumor growth.

Influence of primary tumor site on lymphocyteantitumor activity

Clinical Stage IV-S neuroblastoma involving a primary, the liver, bone marrow, and/or skin has a favorable prognosis despite a considerable tumor burden. In a pilot experiment utilizing mouse C 1300 neuroblastoma, we demonstrated that animals receiving tumor to IV-S sites had a prolonged survival. To analyze the role which liver modulation of tumor might play in an immunologically mediated host-antitumor response, we applied an in vitro lymphocyte blastogenesis assay. Host-tumor response as reflected by blastogenesis and as quantified by tritiated thymidine incorporation into DNA demonstrated that normal lymphocytes were stimulated to a greater degree by subcutaneous site tumor than by tumor from the liver (260.7 +/- 71.9 vs. -54.2 +/- 194.3 CPM, p less than 0.05). Sensitized lymphocytes harvested from liver tumor bearers demonstrated a greater response when admixed with subcutaneous tumor in vitro (771.9 +/- 300.4 vs. 45.9 +/- 277.5 CPM, p less than 0.05) and sensitized lymphocytes harvested from subcutaneous tumor bearing animals also demonstrated more in vitro blastogenesis to subcutaneous tumor (577.9 +/- 200.2 vs. 98.9 +/- 154.1 CPM, p less than 0.05). However, host lymphocytes were themselves comparably reactive whether they were harvested from liver tumor or subcutaneous tumor donors (771.9 +/- 300.4 vs. 577.9 +/- 200.2, p = NS). These data suggest that lymphocytes in contact with murine liver neuroblastoma respond less well than when in contact with subcutaneous site tumor, a form of afferent blockade which may account for the propensity of the liver to serve as a site for metastatic disease.

癌と細胞性免疫

Regional axillary lymph nodes, spleen and distant mesenterial lymph nodes were taken out one, two, three and four weeks after isografting methycholanthrene-induced tumor (MC-tumor) on the back under the skin of C3H mice and lymphocytes were prepared from these lymph nodes and spleen. These lymphocytes were then mixed with the primary cultured tumor cells of MC-tumor in the 20:1 ratio, and cultured for 24 and 48 hours in order to determine antitumor activity of the lymphocytes.As a result it has been shown that at an early stage of one week after tumor transplantation a strong antitumor activity appears only in the regional axillary lymph nodes, which weakens gradually thereafter, and as the time elapses two to three weeks, it disappears.In the spleen, a strong antitumor activity can been ovserved in the third week after tumor transplantation, but the activity disappears by the fourth week. In the distant mesenterial lymph nodes, the antitumor activity grows stronger along with lapse of time after the transplantation, which reaches its peak by the fourth week.These findings indicate that antitumor activity of lymphocytes in different sites appears earliest and strongest in the regional lymph nodes, which weakens and disappears as the cancer progresses, which an antitumor activity makes its appearance in further distant lymphatic tissues.