Inflammation Control and Immunotherapeutic Strategies in Comprehensive Cancer Treatment.

Tumor growth and expansion are determined by the immunological tumor microenvironment (TME). Typically, early tumorigenic stages are characterized by the immune system not responding or weakly responding to the tumor. However, subsequent tumorigenic stages witness the tumor promoting its growth and metastasis by stimulating tumor-protective (pro-tumor) inflammation to suppress anti-tumor immune responses. Here, we propose the pivotal role of inflammation control in a successful anti-cancer immunotherapy strategy, implying that available and novel immunotherapeutic modalities such as inflammation modulation, antibody (Ab)-based immunostimulation, drug-mediated immunomodulation, cancer vaccination as well as adoptive cell immunotherapy and donor leucocyte transfusion could be applied in cancer patients in a synergistic manner to amplify each other's clinical effects and achieve robust anti-tumor immune reactivity. In addition, the anti-tumor effects of immunotherapy could be enhanced by thermal and/or oxygen therapy. Herein, combined immune-based therapy could prove to be beneficial for patients with advanced cancers, as aiming to provide long-term tumor cell/mass dormancy by restraining compensatory proliferation of surviving cancer cells observed after traditional anti-cancer interventions such as surgery, radiotherapy, and metronomic (low-dose) chemotherapy. We propose the Inflammatory Prognostic Score based on the blood levels of C-reactive protein and lactate dehydrogenase as well as the neutrophil-to-lymphocyte ratio to effectively monitor the effectiveness of comprehensive anti-cancer treatment.

Oxygen therapy in traditional and immunotherapeutic treatment protocols of cancer patients: current reality and future prospects.

INTRODUCTION: The metabolic environment in ischemic and hypoxic tumors is known to contribute to cancer progression. Importantly, peculiar metabolic changes occurring in malignant cells (the increased glycolysis and the hampered Krebs cycle) may contribute to decreased antioxidant-dependent defense in ischemic and hypoxic tumors. AREAS COVERED: In the clinic, oxygen saturation of tumors is usually achieved by the application of water-soluble ozone and hyperbaric oxygen therapy. Tumor oxygenation has been shown to inhibit tumor growth and potentiate anti-tumor effects of chemoradiotherapy in animal experiments and the clinical setting. Tumor oxygenation could enhance anti-tumor effects achieved by tumor blood vessel occlusion or angiostatic therapy. EXPERT OPINION: Owing to a profound influence of ROS on both the innate and adaptive immunity, oxygen therapy, when combined simultaneously or sequentially with immunotherapeutic interventions (such as immune checkpoint inhibition, drug-induced immunostimulation, adoptive cell therapy, hyperthermia, etc.), could be considered as a novel highly-effective clinical biological approach to cancer treatment.

Immune memory limits human longevity: the role of memory СD4+ T cells in age-related immune abnormalities.

Introduction: With age, the proportion of memory T cells increases, while the proportion and number of naive T cell decreases. Memory T cells are more sensitive to antigenic stimulation and less dependent on co-stimulation signals, as compared to naïve T cells. Differentiation of naïve T cells into memory T cells is accompanied by an increase in T cell reactivity to self-peptide/MHC complexes, which allowed for positive selection of their naïve precursors in the thymus.Areas covered: We envisage that in geriatric age memory Th1-type autoreactivity leads to age-associated immune hyporeactivity, atherosclerosis, and degenerative neuropathology, such as Alzheimer's and Parkinson's diseases, whereas autoreactive memory Th2 cells could promote tumorigenesis.Expert option: Stimulation of adaptive immunoregulatory mechanisms by polyclonal T-cell vaccination could constrain the development of age-related T-cell autoreactivity surplus. Another approach to immune system 'rejuvenation' could involve adoptive cell transfer of naïve T cells with a view to restrain the expansion of pathological memory T cells and support immune responsiveness to novel antigenic challenges. The proposed concept conjectures the occurrence of a hard-wired immunological clock that could determine the duration of life, which theoretically could be subject to immune-based therapy.

Directs effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on adaptive immunogenesis.

Background: We studied direct effects of human granulocyte-macrophage colony stimulating factor (GM-CSF) on phenotypical characteristics and cytokine-production of non-activated and activated human monocytes/macrophages (Mc/Mphs) and T cells.Methods: Purified Mc/Mphs were activated by bacterial lipopolysaccharide (LPS, 1 µg/ml) for 24 h, while T cells were activated by particles conjugated and antibodies (Abs) against human CD2, CD3, and CD28 for 48 h.Results: GM-CSF treatment (0.01-10 ng/ml) was shown to reduce percentages of CD197 (CCR7)-positive cells in non-activated Mph cultures, without affecting significantly CD14+ (LPS co-receptor), CD16+ (FcγRIII, low-affinity Fc-receptor), CD119+ (interferon-gamma receptor 1), and CD124+ (IL4 receptor α-subunit) cells. In addition, GM-CSF reduced relative numbers of CD197+ cells, as well as CD14+, CD16+, and CD119+ cells in activated Mph cultures without affecting CD124+ cell distribution. GM-CSF at the highest dose of 10 ng/ml enhanced TNF-α and IL-6 (but not IL-1ß and IL-10) production in activated Mc/Mphs. In activated T cell cultures, GM-CSF at 0.1-1.0 ng/ml augmented CD38+ cell numbers in naïve СD45RA+/СD197+ and central memory СD45RA-/СD197+ cell subsets, with no effect on effector СD45RA-/СD197- and terminally differentiated effector СD45RA+/СD197- cells. GM-CSF at a low dose (0.01 ng/ml) down-regulated INF-γ production, while at a high dosage (10.0 ng/ml) up-regulated IL-2 and IL-4 production.Conclusion: In general, the results suggest that GM-CSF is able to facilitate the implication of both Mph and T cells in the adaptive immunogenesis.

Direct anti-inflammatory effects of granulocyte colony-stimulating factor (G-CSF) on activation and functional properties of human T cell subpopulations in vitro.

We investigated the direct effects of human granulocyte colony-stimulating factor (G-CSF) on functionality of human T-cell subsets. CD3+ T-lymphocytes were isolated from blood of healthy donors by positive magnetic separation. T cell activation with particles conjugated with antibodies (Abs) to human CD3, CD28 and CD2 molecules increased the proportion of cells expressing G-CSF receptor (G-CSFR, CD114) in all T cell subpopulations studied (CD45RA+/CD197+ naive T cells, CD45RA-/CD197+ central memory T cells, CD45RA-/CD197- effector memory T cells and CD45RA+/CD197- terminally differentiated effector T cells). Upon T-cell activation in vitro, G-CSF (10.0 ng/ml) significantly and specifically enhanced the proportion of CD114+ T cells in central memory CD4+ T cell compartment. A dilution series of G-CSF (range, 0.1-10.0 ng/ml) was tested, with no effect on the expression of CD25 (interleukin-2 receptor α-chain) on activated T cells. Meanwhile, G-CSF treatment enhanced the proportion of CD38+ T cells in CD4+ naïve T cell, effector memory T cell and terminally differentiated effector T cell subsets, as well as in CD4- central memory T cells and terminally differentiated effector T cells. G-CSF did not affect IL-2 production by T cells; relatively low concentrations of G-CSF down-regulated INF-γ production, while high concentrations of this cytokine up-regulated IL-4 production in activated T cells. The data obtained suggests that G-CSF could play a significant role both in preventing the development of excessive and potentially damaging inflammatory reactivity, and in constraining the expansion of potentially cytodestructive T cells.

Direct effects of interleukin-8 on growth and functional activity of T lymphocytes.

CD3+ T-lymphocytes were isolated from the normal donors by positive magnetic separation. Activation of the T cells with particles conjugated with antibodies to CD3, СD28 and СD2 molecules led to a marked increase in T-cell production of interleukine-8 (IL-8). We present evidence that IL-8 receptor α-chain (CXCR1, CD181) is expressed on the cell surface of 13.3% T cells. Activation of T-lymphocytes resulted in significant enhancement of CD181+ cells both in naive CD4+ T cell and terminally differentiated effector CD4+ T cell compartments with concomitant reduction of CD181+ cells in effector memory CD4+ T cell subset. The level of T cell activation was assessed judging from the surface expression of CD25 (IL-2 receptor α-chain). We demonstrate that IL-8 treatment (0.01-10.0ng/ml concentration range) reduced the activation status of both CD4- and CD4+ effector memory T cells, as well as terminally differentiated effector T cells, without significantly affecting the activation of naive T cells or central memory T cells. In addition, IL-8 up-regulated IL-2 and down-regulated IL-10 production by activated T cells, with no effect on interferon-gamma (IFN-γ) and IL-4 production. Data obtained suggests the importance of IL-8 in the direct regulation of adaptive T cell reactivity.