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During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.

Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts, or cancer cells. The IL1B gene is induced after “priming” of the cells and a second signal is required to allow IL-1β maturation by inflammasome-activated caspase-1. IL-1β is then released and leads to transcription of target genes through its ligation with IL-1R1 on target cells. IL-1β expression and maturation are guided by gene polymorphisms and by the cellular context. In cancer, IL-1β has pleiotropic effects on immune cells, angiogenesis, cancer cell proliferation, migration, and metastasis. Moreover, anti-cancer treatments are able to promote IL-1β production by cancer or immune cells, with opposite effects on cancer progression. This raises the question of whether or not to use IL-1β inhibitors in cancer treatment.

In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti-PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti-TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti-PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g., by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors.

Natural Killer (NK) cells are innate immune cells that play a pivotal role as first line defenders in the anti-tumor response. To prevent tumor development, NK cells are searching for abnormal cells within the body and appear to be key players in immunosurveillance. Upon recognition of abnormal cells, NK cells will become activated to destroy them. In order to fulfill their anti-tumoral function, they rely on the secretion of lytic granules, expression of death receptors and production of cytokines. Additionally, NK cells interact with other cells in the tumor microenvironment. In this review, we will first focus on NK cells’ activation and cytotoxicity mechanisms as well as NK cells behavior during serial killing. Lastly, we will review NK cells’ crosstalk with the other immune cells present in the tumor microenvironment.

Key Points The dominant rationale to generate new (and to assess old) anticancer chemotherapeutic agents is to determine their cell-autonomous effects — that is, their capacity to reduce the growth (cytostasis) and to induce the death (cytotoxicity) of tumour cells in vitro and in vivo (usually in immunodeficient mice that have been xenotransplanted with human tumours). Experimental data obtained from immuncompetent mice and clinical data obtained from patients indicate that several chemotherapeutic agents have unexpected effects on the immune system. At least in some instances, these 'side effects' can contribute to the therapeutic effects of anticancer drugs. A non-exhaustive list of examples of drugs that combine anticancer and immunostimulatory effects includes: imatinib mesylate, cyclophosphamide, anthracyclines and 5-fluorouracil. Imatinib mesylate, a protein tyrosine kinase inhibitor, can induce caspase-independent death of tumour cells, can enhance natural killer (NK)-cell activities and can induce the expansion of a specific NK-cell subset that also bears dendritic-cell markers, known as interferon-producing killer dendritic cells, which in turn have tumoricidal effects. Cyclophosphamide, a DNA-alkylating agent, induces non-apoptotic cell death of tumour cells and T cells. In addition, it can deplete regulatory T cells, thereby overriding their antitumour immune responses. Anthracyclines can induce an immunogenic variant of apoptosis in tumour cells, thereby eliciting an antitumour immune response that is mediated by dendritic cells and cytotoxic T cells. 5-Fluorouracil and other p53-activating cytotoxic drugs promote increased expression of tumour-associated antigens and co-stimulatory molecules on tumour cells. These agents illustrate the therapeutic feasibility of an 'immunogenic chemotherapy'; that is, a programme of chemotherapy that aims at stimulating the antitumour immune response as a warranted side effect of the therapy. Moreover, it might be possible to combine agents that induce direct cancer-cell-specific and immunostimulatory effects for an optimal therapeutic outcome. Theoretically, the induction of immunogenic cancer-cell death or other immunogenic effects should be one of the aims of anticancer chemotherapy so that the immune system can contribute through a 'bystander effect' to eradicate chemotherapy-resistant cancer cells and cancer stem cells. Here, the authors describe how the antitumour effects of many conventional cancer treatments involve the immune system, by promoting immunogenic tumour-cell death or by direct stimulation of immune cells. Taking advantage of this 'bystander effect' may help in the fight against cancer. Accumulating evidence indicates that the innate and adaptive immune systems make a crucial contribution to the antitumour effects of conventional chemotherapy-based and radiotherapy-based cancer treatments. Moreover, the molecular and cellular bases of the immunogenicity of cell death that is induced by cytotoxic agents are being progressively unravelled, challenging the guidelines that currently govern the development of anticancer drugs. Here, we review the immunological aspects of conventional cancer treatments and propose that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies.

Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8 + T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity. Lipid droplets (LD) accumulation correlates with colorectal cancer (CRC) relapse. Here the authors show that chemotherapy induces LD synthesis via acyltransferase LPCAT2 which, in turn, promotes chemoresistance via LD accumulation both in vitro and in vivo by blocking chemotherapy-induced ER stress.

The accumulation of regulatory T cells (Tregs) at high density in various human carcinomas is generally associated with a poor prognosis, as expected from their capacity to inhibit antitumor immunity. Surprisingly, in patients bearing colorectal carcinoma (CRC), high regulatory T-cell infiltration is associated with a favorable prognosis, as shown by the analysis of seven clinical studies. To explain this paradox, we emphasize a putative role of the dense microbiological flora present in the large intestine with a trend toward translocation through the tumor. This microbiological hazard requires a T-cell-mediated inflammatory anti-microbial response that involves Th17 cells and can thereby promote cancer growth. This Th17-cell-dependent proinflammatory and tumor-enhancing response can be attenuated by Tregs, thus constituting a possible explanation for their favorable role in CRC prognosis. The link between a high density of FOXP3-positive cells in CRC immune infiltrates and favorable prognosis should lead us to consider tumor infiltrating Tregs as allies to be respected, rather than enemies to be destroyed during trials of CRC treatment.

Checkpoint blockade immunotherapy is a therapeutic revolution in cancer treatment. However, only 5% of patients with metastatic colorectal cancer benefit from these therapies, and these tumors genetically harbored microsatellite instability status. In contrast, tumors with stable microsatellites are considered resistant to immunotherapy, and standard treatment with chemotherapies is standard of care, with few chances of curative intent. In a recent clinical trial, we demonstrated that the combination of two chemotherapies with two immunotherapies promotes the recruitment and activation of the adaptive immune system at the tumor level, resulting in clinical benefit in a significant number of patients. In parallel, a biological study revealed biomarkers of response, including CTLA-4 expression and induction of a tumor-specific immune response.

Immunotherapy using checkpoint inhibitor targeting PD-1 and PD-L1 revolutionized the treatment of microsatellite instable metastatic colon cancer. Such treatment is now a standard of care for these patients. However, when used as monotherapy checkpoint inhibitors targeting PD-1 and PD-L1 are not effective in metastatic colorectal cancer patients with microsatellite stable tumors. Recent advances in biology provide a rationale for this intrinsic resistance and support the evaluation of combination therapy to reverse resistance. This article will highlight recent findings on the mechanism of intrinsic resistance and recent advances in clinical trials for combination therapy.