Cancer immunotherapy through the prism of adaptation: Will Achilles catch the tortoise?

There is no secret that despite the rapid development of new methods of cancer therapy, we still are not able to completely destroy the tumor. Every time we attack the tumor, the tumor neutralizes our attempts. Carcinogenesis can be presented as a tree whose branches are different pro-tumor mechanisms and whose trunk is a biological phenomenon that "feeds" those branches. A tree can be destroyed in two ways: either by cutting a branch for a branch without a guarantee that new branches will not grow, or cutting down the trunk and letting the branches wither away. To cut down the trunk, it is necessary to understand the nature of the biological phenomenon, which helps the tumor to avoid attack by the immune system, drugs and immunotherapy. The clue is that the pro-tumor mechanisms are united by one goal - to increase the resistance of the tumor cell to immune factors and drugs. A phenomenon that improves cell resistance is well known in biology - adaptation. If the immunity does not immediately destroy the tumor cell, the cell begins to adapt to it. Our hypothesis is that short range adaptation to immune factors plays a role in the formation of tumor tolerance for immunity and immunotherapy. This gives rise to the idea of reducing the survival of tumor cells by disrupting adaptation mechanisms. Indeed, "turning off" the immune system for a period of time before therapy and applying immunotherapy only to tumor cells that have lost their increased resistance could be a new approach to increase the effectiveness of immunotherapy.

Macrophages Reprogrammed In Vitro Towards the M1 Phenotype and Activated with LPS Extend Lifespan of Mice with Ehrlich Ascites Carcinoma.

BACKGROUND The majority of tumors trigger macrophage reprogramming from an anti-tumor M1 phenotype towards a pro-tumor M2 phenotype. The M2 phenotype promotes tumor growth. We hypothesized that increasing the number of M1 macrophages in a tumor would limit carcinogenesis and extend the lifespan of the tumor host. The aim of this study was to verify this hypothesis in Ehrlich ascites carcinoma (EAC). The objectives were to evaluate effects of 1) EAC on a macrophage phenotype and NO-producing macrophage activity in vivo; 2) ascitic fluid from mice with EAC on a macrophage phenotype and NO-producing macrophage activity in vitro; and 3) in vitro reprogrammed M1 macrophages on lifespan of mice with EAC. MATERIAL AND METHODS The study was conducted using C57BL/6J mice. RESULTS Concentration of nitrite, a stable NO metabolite and an index of NO production, was measured spectrophotometrically. Shifts of macrophage phenotype were assessed by changes in NO production as well as by amounts of CD80, a marker of M1 phenotype, and CD206, a marker of M2 phenotype. The CD markers were measured by flow cytometry. Macrophages were reprogrammed towards the M1 phenotype using two reprogramming factors: 0% FBS and 20 ng/ml IFN-γ. The study results showed that 1) EAC inhibited the macrophage NO production in vivo and reprogrammed macrophages towards the M2 phenotype; 2) ascitic fluid of mice with EAC inhibited the macrophage NO production in vitro and reprogrammed macrophages towards the M2 phenotype; and 3) injection of in vitro reprogrammed M1 macrophages into mice with EAC significantly increased the lifespan of mice. CONCLUSIONS These findings suggest that promising biotechnologies for restriction of tumor growth could be developed based on the in vitro macrophage reprogramming.

Nitric oxide production and intensity of free radical processes in young men with high normal and hypertensive blood pressure.

BACKGROUND: Young individuals with high normal blood pressure (HNBP) are at risk for hypertension. The aim of our study was to compare NO production and the intensity of free radical processes in young males with different BP levels. MATERIAL/METHODS: Male subjects aged 18-45 years with normal BP, HNBP, and hypertension underwent physical and cardiological examination. NO production was evaluated by measuring plasma nitrite and nitrate (NOx) and 24-hour urinary excretion of NOx. Lipid peroxidation (LP) intensity and serum antioxidant activity (AOA) were measured using the biochemiluminescence method. RESULTS: HNBP was associated with increased 24-hour systolic BP (SBP), diastolic BP (DBP), SBP and DBP variability, plasma and 24-hour urinary NOx and LP intensity, and decreased total AOA as compared to normotensive controls. We observed a direct nonlinear correlation between plasma NOx and SBP and between 24-hour urinary NOx and DBP, and a close inverse correlation between LP intensity and AOA in patients with HNBP. In the presence of two cardiovascular risk factors (smoking and obesity), patients with HNBP displayed higher LP intensity and lower levels of NOx than in both nonsmokers with normal body weight and control subjects. In hypertensive patients, SBP, DBP and LP intensity inversely correlated with plasma and urinary NOx. CONCLUSIONS: Activation of LP processes and depression of AOA proceed in parallel with declining NO production and severity of hypertension. Early correction of the revealed disorders before the appearance of clinical symptoms may be promising in terms of prevention and treatment of cardiovascular disease.