Mechanisms of immune modulation in the tumor microenvironment and implications for targeted therapy

Cancer; Immunosuppression mechanisms; Tumor microenvironmentCáncer; Mecanismos de inmunosupresión; Microambiente tumoralCàncer; Mecanismes d'immunosupressió; Microambient tumoralThe efficacy of cancer therapies is limited to a great extent by immunosuppressive mechanisms within the tumor microenvironment (TME). Numerous immune escape mechanisms have been identified. These include not only processes associated with tumor, immune or stromal cells, but also humoral, metabolic, genetic and epigenetic factors within the TME. The identification of immune escape mechanisms has enabled the development of small molecules, nanomedicines, immune checkpoint inhibitors, adoptive cell and epigenetic therapies that can reprogram the TME and shift the host immune response towards promoting an antitumor effect. These approaches have translated into series of breakthroughs in cancer therapies, some of which have already been implemented in clinical practice. In the present article the authors provide an overview of some of the most important mechanisms of immunosuppression within the TME and the implications for targeted therapies against different cancers

Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer

Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients’ prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells

Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer

Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients’ prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells

The Predictive Role of Serum Levels of Soluble Cell Adhesion Molecules (sCAMs) in the Therapy of Advanced Breast Cancer—A Single-Centre Study

Background and Objectives: Soluble cell adhesion molecules (sCAMs) play a significant role in the metastatic potential of breast cancer (BC). They might block lymphocytes and promote angiogenesis and migration of cancer cells. We assessed the usefulness of sCAMs in the prognosis and monitoring of the progression of advanced BC. Materials and Methods: We assessed soluble E-selectin, P-selectin, VCAM-1, ICAM-1, EpCAM, IL-6Ra, TNF-R1, and TNF-R2 in 39 women with aBC. Blood samples were obtained at the beginning of the treatment and after 2 months. Results: The median progression-free survival (PFS) was 9 months, and overall survival (OS) was 27 months. The higher levels of sICAM-1 (HR = 2.60, p = 0.06) and lower levels of sEpCAM (HR = 2.72, p < 0.05) were associated with faster progression of aBC. High levels of sEpCAM through the follow-up period were significantly associated with a lower risk of progression (HR = 0.40, p < 0.01). We found the independent predictive value of higher than median sICAM-1 levels for PFS (HR = 2.07, p = 0.08) and of sVCAM-1 levels for OS (HR = 2.59, p < 0.05). Conclusions: Our data support the predictive value of sICAM-1 and sVCAM-1 and suggest that they could become markers for tailoring new therapies in aBC. sEpCAM level could be used as an early indicator of response to the therapy

Stężenie VEGF-A, sVEGFR-2 i galektyny-3 w surowicy pacjentek z rakiem piersi nie koreluje ze stopniem zaawansowania klinicznego, wielkością guza ani skutecznością chemioterapii okołooperacyjnej

INTRODUCTION: Tumor angiogenesis is regulated by numerous cytokines and growth factors, with vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor 2 (sVEGFR-2), and galectin-3, playing a significant role in the process. There are conflicting data concerning changes in serum VEGF, sVEGFR-2 and galectin-3 levels in breast cancer (BC) patients during the course of the disease and chemotherapy (CTH). This study aimed to assess the serum levels of VEGF-A, sVEGFR-2, and galectin-3 in women starting adjuvant and neoadjuvant therapy for BC, and their changes during the treatment. MATERIAL AND METHODS: This single-center study enrolled 98 women with non-metastatic BC, including 56 who started adjuvant therapy and 42 preoperative (neoadjuvant/induction) CTH. The serum levels of VEGF-A, sVEGFR-2, and galectin-3 were assessed at the beginning of CTH and after 2 subsequent months. RESULTS: There were no significant differences in the serum levels of VEGF-A, sVEGFR-2, and galectin-3 between patients starting adjuvant and preoperative therapy. In addition, there was no correlation between the serum levels and the clinical stage of BC. During CTH, a significant increase in VEGF-A, sVEGFR-2, and galectin-3 was noted, however, without a predictive significance for obtaining complete pathological response (pCR) both for the initial levels and changes in the serum levels. CONCLUSIONS: The serum levels of VEGF-A, sVEGFR-2, and galectin-3 do not correlate with the clinical stage or tumor size in patients with non-metastatic BC. The baseline levels of VEGF-A, sVEGFR-2 and galectin-3, and the observed increase in the serum levels of VEGF-A and sVEGFR-2 during CTH do not predict its efficacy.WSTĘP: Angiogeneza nowotworowa jest procesem regulowanym przez wiele cytokin i czynników wzrostu, spośród których znaczącą rolę odgrywają czynnik wzrostu śródbłonka naczyń (vascular endothelial growth factor – VEGF), drugi rozpuszczalny receptor dla śródbłonkowego czynnika wzrostu (soluble vascular endothelial growth factor recep-tor 2 – sVEGFR-2) i galektyna-3. Dane literaturowe dotyczące oceny zmian stężenia VEGF, sVEGFR-2 oraz galekty-ny-3 w trakcie chemioterapii (chemotherapy – CTH) raka piersi (breast cancer – BC) są niejednoznaczne. Celem niniej-szej pracy była analiza stężenia VEGF-A, sVEGFR-2 oraz galektyny-3 w surowicy pacjentek z rakiem piersi, rozpoczynających adjuwantową i neoadjuwantową chemioterapię oraz ocena zmian stężenia tych cytokin w trakcie leczenia. MATERIAŁ I METODY: Jednoośrodkowe badanie objęło 98 pacjentek z miejscowo zaawansowanym rakiem piersi, w tym 56 poddanych adjuwantowej i 42 neoadjuwantowej terapii. Stężenie VEGF-A, sVEGFR-2 i galektyny-3 w surowicy krwi oceniono na początku leczenia oraz po 2 miesiącach terapii. WYNIKI: Nie stwierdzono istotnych różnic pomiędzy stężeniami VEGF-A, sVEGFR-2 oraz galektyny-3 w surowicy pacjentek poddanych adjuwantowej i neoadjuwantowej chemioterapii. Nie wykazano również zależności między stężeniem tych cytokin w surowicy a stopniem zaawansowania klinicznego raka piersi. W trakcie przedoperacyjnej chemio-terapii odnotowano znaczące zwiększenie stężenia VEGF-A, sVEGFR-2 i galektyny-3, jednakże zarówno wyjściowe stężenia cytokin, jak i zmiany w czasie nie miały znaczenia predykcyjnego dla uzyskania całkowitej odpowiedzi pato-ogicznej. WNIOSKI: Stężenia VEGF-A, sVEGFR-2 oraz galektyny-3 w surowicy nie korelują ze stopniem zaawansowania klinicznego ani masą nowotworu u pacjentek z miejscowo zaawansowanym rakiem piersi. Wyjściowe stężenia VEGF-A, sVEGFR-2 i galektyny-3 oraz zaobserwowany wzrost stężeń tych cytokin w surowicy w trakcie chemioterapii nie mają wartości predykcyjnej dla jej skuteczności

Serum cytokine profile as a potential prognostic tool in colorectal cancer patients one center study

AIM: Comparison of 14 cytokines levels between a control group and prospectively enrolled CRC patients to confirm their significance in CRC development. We tested if a model based on 14 cytokines levels could predict prognosis in Caucasian CRC patients treated with 5-FU based chemotherapy. BACKGROUND: Novel prognostic tools in colorectal cancer (CRC) are necessary to optimize treatment, reduce toxicity and chemotherapy (CHT) costs. MATERIALS AND METHODS: We assessed prognostic significance of 14 cytokines: IL-1 beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-17A in 75 prospectively enrolled CRC patients before initiation of palliative or adjuvant CHT and in 22 control subjects. Readings were taken using the Bio-Plex 200 System. Response to treatment was assessed after 6 months from initiation of CHT. The treated group was divided depending on the response into a progressors (death, progression of disease) and non-progressors group (stable disease, partial response, complete response). RESULTS: We found that increased concentration of IL-8 was a negative prognostic factor in the whole group and palliative subgroup, whereas increased level of IL-10, IL-7, and IL-12p70 was a negative predictor in the adjuvant group CHT. CONCLUSIONS: We proposed a statistical model based on circulating cytokine levels, showing a good prognostic value in prediction of the response to CHT (AUC = 0.956). The model, including combined IL-2, IL-8, IL-10 and IL-13 levels, established in the whole treated group, should be validated in larger trials

Serum cytokine profile as a potential prognostic tool in colorectal cancer patients – one center study

AimComparison of 14 cytokines levels between a control group and prospectively enrolled CRC patients to confirm their significance in CRC development. We tested if a model based on 14 cytokines levels could predict prognosis in Caucasian CRC patients treated with 5-FU based chemotherapy.BackgroundNovel prognostic tools in colorectal cancer (CRC) are necessary to optimize treatment, reduce toxicity and chemotherapy (CHT) costs.Materials and MethodsWe assessed prognostic significance of 14 cytokines: IL-1 beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-17A in 75 prospectively enrolled CRC patients before initiation of palliative or adjuvant CHT and in 22 control subjects. Readings were taken using the Bio-Plex 200 System. Response to treatment was assessed after 6 months from initiation of CHT. The treated group was divided depending on the response into a progressors (death, progression of disease) and non-progressors group (stable disease, partial response, complete response).ResultsWe found that increased concentration of IL-8 was a negative prognostic factor in the whole group and palliative subgroup, whereas increased level of IL-10, IL-7, and IL-12p70 was a negative predictor in the adjuvant group CHT.ConclusionsWe proposed a statistical model based on circulating cytokine levels, showing a good prognostic value in prediction of the response to CHT (AUC = 0.956). The model, including combined IL-2, IL-8, IL-10 and IL-13 levels, established in the whole treated group, should be validated in larger trials

Vitamin D and Its Metabolites Status before and during Chemotherapy in Caucasian Breast Cancer Patients

Background: The predictive role of vitamin D (VD) in breast cancer (BC) patients’ survival is still being investigated. This paper aims to evaluate the changes in VD metabolites during chemotherapy (CTH) and the predictive role of VD status in Caucasian BC patients treated with CTH. Methods: Vitamin D and its metabolites were assessed with reference LC–MS/MS methodology in 98 consecutive BC patients starting CHT, after 3 and 6 months, and compared to the control group. Results: The frequency of VD deficiency in BC patients was greater than in the control group (56.1% vs. 37.2%). After 6 months of CTH, the number of VD-deficient BC patients slightly increased to 60%. The concentrations of VD active forms [25(OH)D2, 25(OH)D3], and catabolites [24,25(OH)2D3 and 3-epi-25(OH)D3] decreased after 3 and 6 months of CTH compared to the baseline values. Strong positive correlations between concentrations of 3-epi-25(OH)D3 and 25(OH)D in both groups were found. Similar correlations were also observed between 24,25(OH)2D3 and 25(OH)D levels. Kaplan–Meier survival analysis showed significantly longer survival in BC patients without deficiency (>20 ng/mL) at baseline (HR = 2.44 (95% CI 1.07–5.59), p = 0.026). Conclusions: (1) Our data provide further evidence that BC patients before CTH are more VD-deficient than the general population and this deficiency increases further during CTH treatment, as observed using the reference LC-MS methodology. (2) Presented results show that VD catabolism is not affected in BC patients. (3) The poorer survival in VD-deficient BP patients supports the importance of VD supplementation in BC patients with 25(OH)D levels below 20 ng/mL

Intracellular DNA sensing by neutrophils and amplification of the innate immune response.

Peer reviewed: TrueAs the first responders, neutrophils lead the innate immune response to infectious pathogens and inflammation inducing agents. The well-established pathogen neutralizing strategies employed by neutrophils are phagocytosis, the action of microbicide granules, the production of ROS, and the secretion of neutrophil extracellular traps (NETs). Only recently, the ability of neutrophils to sense and respond to pathogen-associated molecular patterns is being appreciated. This review brings together the current information about the intracellular recognition of DNA by neutrophils and proposes models of signal amplification in immune response. Finally, the clinical relevance of DNA sensing by neutrophils in infectious and non-infectious diseases including malignancy are also discussed

Mechanisms of immune modulation in the tumor microenvironment and implications for targeted therapy.

Peer reviewed: TrueThe efficacy of cancer therapies is limited to a great extent by immunosuppressive mechanisms within the tumor microenvironment (TME). Numerous immune escape mechanisms have been identified. These include not only processes associated with tumor, immune or stromal cells, but also humoral, metabolic, genetic and epigenetic factors within the TME. The identification of immune escape mechanisms has enabled the development of small molecules, nanomedicines, immune checkpoint inhibitors, adoptive cell and epigenetic therapies that can reprogram the TME and shift the host immune response towards promoting an antitumor effect. These approaches have translated into series of breakthroughs in cancer therapies, some of which have already been implemented in clinical practice. In the present article the authors provide an overview of some of the most important mechanisms of immunosuppression within the TME and the implications for targeted therapies against different cancers