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Cycling hypoxia (cyH), neo-angiogenesis, and tumor-associated macrophages are key features of the tumor microenvironment. In this study, we demonstrate that cyH potentiates the induction by unpolarized and M1-like macrophages of endothelial inflammatory phenotype and adhesiveness for monocytes and cancer cells. This process triggers a positive feedback loop sustaining tumor inflammation. This work opens the door for innovative therapeutic strategies to treat tumor inflammation and metastasis.In cancers, the interaction between macrophages and endothelial cells (ECs) regulates tumor inflammation and metastasis. These cells are both affected by cycling hypoxia (cyH), also called intermittent hypoxia, a feature of the tumor microenvironment. cyH is also known to favor tumor inflammation and metastasis. Nonetheless, the potential impact of cyH on the dialog between macrophages and ECs is still unknown. In this work, the effects of unpolarized, M1-like, and M2-like macrophages exposed to normoxia, chronic hypoxia (chH), and cyH on endothelial adhesion molecule expression, pro-inflammatory gene expression, and EC adhesiveness for monocytes and cancer cells were investigated. cyH increased the ability of unpolarized and M1-like macrophages to induce EC inflammation and to increase the expression of the EC endothelial adhesion molecule ICAM1, respectively. Unpolarized, M1-like, and M2-like macrophages were all able to promote EC adhesive properties toward cancer cells. Furthermore, the ability of macrophages (mostly M1-like) to shift EC phenotype toward one allowing cancer cell and monocyte adhesion onto ECs was potentiated by cyH. These effects were specific to cyH because they were not observed with chH. Together, these results show that cyH amplifies the effects of macrophages on ECs, which may promote tumor inflammation and metastasis.

Immunogenic cell death (ICD) is a rapidly growing research area representing one of the emerging therapeutic strategies of cancer immunotherapy. ICD is an umbrella term covering several cell death modalities including apoptosis, necroptosis, ferroptosis and pyroptosis, and is the product of a balanced combination of adjuvanticity (damage-associated molecular patterns and chemokines/cytokines) and antigenicity (tumor associated antigens). Only a limited number of anti-cancer therapies are available to induce ICD in experimental cancer therapies and even much less is available for clinical use. To overcome this limitation, nanomaterials can be used to increase the immunogenicity of cancer cells killed by anti-cancer therapy, which in themselves are not necessarily immunogenic. In this review, we outline the current state of knowledge of ICD modalities and discuss achievements in using nanomaterials to increase the immunogenicity of dying cancer cells. The emerging trends in modulating the immunogenicity of dying cancer cells in experimental and translational cancer therapies and the challenges facing them are described. In conclusion, nanomaterials are expected to drive further progress in their use to increase efficacy of anti-cancer therapy based on ICD induction and in the future, it is necessary to validate these strategies in clinical settings, which will be a challenging research area.

Recent studies have highlighted the potential of photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The clinical use of photosensitizers (PS) to stimulate an anticancer immune response, and not to sterilize tumor cells, may however require some optimizations. Here, we examined how the dose of PS and the scheduling of PDT influence the generation of danger-associated molecular patterns proteins (DAMPs) and favor T cell antitumor activity. We found that upon photoactivation, a low dose of the non-porphyrinic PS OR141 was more prone than higher doses to induce DAMPs in vitro and to inhibit squamous cell carcinoma growth in mice. We further used PDT-killed cancer cells to prime dendritic cells (DC) and stimulate their maturation to evaluate whether the timing of their injection could influence the antitumor effects of radiotherapy. While PDT-based DC vaccination administered before radiotherapy failed to increase tumor growth inhibition, DC injection in the peri-radiotherapy period led to significant tumor growth delay, emphasizing the importance of the coincidence of T cell activation and alterations of the tumor bed. In conclusion, the use of OR141 as a bona fide ICD inducer led us to unravel both the non-linear relationship between PS concentration and PDT-induced antitumor immune response, and the value of an optimal timing of PDT when co-administered with conventional anticancer therapies. This study therefore stresses the necessity of adapting the clinical use of PDT when the goal is to promote an immune response and identifies PDT-based DC vaccination as a suitable modality to reach such objective.

Background and Purpose: The anti-diabetic biguanide drugs metformin and phenformin exhibit antitumor activity in various models. However, their radiomodulatory effect under hypoxic conditions, particularly for phenformin, is largely unknown. This study therefore examines whether metformin and phenformin as mitochondrial complex I blockades could overcome hypoxic radioresistance through inhibition of oxygen consumption.Materials and Methods: A panel of colorectal cancer cells (HCT116, DLD-1, HT29, SW480, and CT26) was exposed to metformin or phenformin for 16 h at indicated concentrations. Afterward, cell viability was measured by MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) were detected by flow cytometry. Phosphorylation of AMP-activated protein kinase (AMPK) was examined by western blot. Mitochondria complexes activity and oxygen consumption rate (OCR) were measured by seahorse analyzer. The radiosensitivity of tumor cells was assessed by colony formation assay under aerobic and hypoxic conditions. The in vitro findings were further validated in colorectal CT26 tumor model.Results: Metformin and phenformin inhibited mitochondrial complex I activity and subsequently reduced OCR in a dose-dependent manner starting at 3 mM and 30 μM, respectively. As a result, the hypoxic radioresistance of tumor cells was counteracted by metformin and phenformin with an enhancement ratio about 2 at 9 mM and 100 μM, respectively. Regarding intrinsic radioresistance, both of them did not exhibit any effect although there was an increase of phosphorylation of AMPK and ROS production. In tumor-bearing mice, metformin or phenformin alone did not show any anti-tumor effect. While in combination with radiation, both of them substantially delayed tumor growth and enhanced radioresponse, respectively, by 1.3 and 1.5-fold.Conclusion: Our results demonstrate that metformin and phenformin overcome hypoxic radioresistance through inhibition of mitochondrial respiration, and provide a rationale to explore metformin and phenformin as hypoxic radiosensitizers.

Photodynamic therapy (PDT) is used to treat malignancies and precancerous lesions. Near-infrared light delivered by lasers was thought for a while to be the most appropriate option to activate photosensitizers, mostly porphyrins, in the depth of the diseased tissues. More recently, however, several advantages including low cost and reduced adverse effects led to consider light emitting diodes (LED) and even daylight as an alternative to use PDT to treat accessible lesions. In this study we examined the capacity of OR141, a recently identified non-porphyrin photosensitizer (PS), to exert significant cytotoxic effects in various models of skin lesions and tumors upon white light activation. Using different cancer cell lines, we first identified LED lamp as a particularly suited source of light to maximize anti-proliferative effects of OR141. We then documented that OR141 diffusion and light penetration into tumor spheroids both reached thresholds compatible with the induction of cell death deep inside these 3D culture models. We further identified Arlasove as a clinically suitable solvent for OR141 that we documented by using Franz cells to support significant absorption of the PS through human skin. Finally, using topical but also systemic administration, we validated growth inhibitory effects of LED-activated OR141 in mouse skin tumor xenograft and precancerous lesions models. Altogether these results open clinical perspectives for the use of OR141 as an attractive PS to treat superficial skin malignant and non-malignant lesions using affordable LED lamp for photoactivation.

Cancers are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These metabolic networks are directly linked with cancer progression, treatment resistance and relapse. Conversely, metabolic alterations in cancer are exploited for anticancer therapy, imaging and personalized medicine. These topics were addressed at the 3rd annual meeting of the International Society of Cancer Metabolism (ISCaM) in Brussels, Belgium, on 26–29 October 2016.