Formyl peptide receptor-1 (FPR1) represses intestinal oncogenesis.

Formyl peptide receptor-1 (FPR1) is a pattern recognition receptor that is mostly expressed by myeloid cells. In patients with colorectal cancer (CRC), a loss-of-function polymorphism (rs867228) in the gene coding for FPR1 has been associated with reduced responses to chemotherapy or chemoradiotherapy. Moreover, rs867228 is associated with accelerated esophageal and colorectal carcinogenesis.

Rs867228 in FPR1 accelerates the manifestation of luminal B breast cancer.

Formyl peptide receptor-1 (FPR1) is a pathogen recognition receptor involved in the detection of bacteria, in the control of inflammation, as well as in cancer immunosurveillance. A single nucleotide polymorphism in , rs867228, provokes a loss-of-function phenotype. In a bioinformatic study performed on The Cancer Genome Atlas (TCGA), we observed that homo-or heterozygosity for rs867228 in (which affects approximately one-third of the population across continents) accelerates age at diagnosis of specific carcinomas including luminal B breast cancer by 4.

A loss-of-function polymorphism in compromises therapeutic outcome in head and neck carcinoma patients.

The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC).

Improved Swiss-rolling method for histological analyses of colon tissue.

Since the introduction of the Swiss-rolling technique by Reilly and Kirsner in 1965, various methodological approaches have been developed for histological analyses of intestinal tissues. Here, we describe an improved protocol for the processing of freshly harvested murine colons that can be extended to other intestinal tissues. With simple tools, this technique allows to tightly wrap the organ throughout the whole length and to keep it in place before fixation, avoiding excessive stiffness of the tissue.

No impact of cancer and plague-relevant polymorphisms on COVID-19.

Formyl peptide receptor 1 (FPR1) is a pattern-recognition receptor that detects bacterial as well as endogenous danger-associated molecular patterns to trigger innate immune responses by myeloid cells. A single nucleotide polymorphism, rs867228 (allelic frequency 19-20%), in the gene coding for FPR1 accelerates the manifestation of multiple carcinomas, likely due to reduced anticancer immunosurveillance secondary to a defect in antigen presentation by dendritic cells. Another polymorphism in , rs5030880 (allelic frequency 12-13%), has been involved in the resistance to plague, correlating with the fact that FPR1 is the receptor for .

Autophagy-mediated metabolic effects of aspirin.

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy.

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of , calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice.

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications.

Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. Both resiquimod and motolimod operate as agonists of Toll-like receptor 7 (TLR7) and/or TLR8, in thus far delivering adjuvant-like signals to antigen-presenting cells (APCs). In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines.

Trial watch: IDO inhibitors in cancer therapy.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", which converts the essential amino acid tryptophan (Trp) into the immunosuppressive metabolite kynurenine (Kyn). While expressed constitutively by some tissues, IDO1 can also be induced in specific subsets of antigen-presenting cells that ultimately favor the establishment of immune tolerance to tumor antigens. At least in part, the immunomodulatory functions of IDO1 can be explained by depletion of Trp and accumulation of Kyn and its derivatives.

Trial watch: STING agonists in cancer therapy.

Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (., in cells exposed to chemotherapy or radiotherapy).

Trial watch: TLR3 agonists in cancer therapy.

Unlabelled: Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates a signal transduction pathway that culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter is essential not only for innate immune responses to infection but also for the initiation of antigen-specific immunity against viruses and malignant cells.

Contribution of annexin A1 to anticancer immunosurveillance.

Mouse cancers lacking the expression of annexin A1 (ANXA1) fail to respond to immunogenic chemotherapies. This has been initially explained by the requirement of extracellular ANXA1 (which is released from dying cancer cells) to engage formyl peptide receptor-1 (FPR1) on dendritic cells (DC) for the establishment of corpse/DC synapses. Here, we show that ANXA1-deficent cancer cells exhibit a defect in the exposure of calreticulin (CALR), which is an important "eat-me" signal, facilitating the phagocytic uptake of dead-cell antigens by DC.

Chemical activation of SAT1 corrects diet-induced metabolic syndrome.

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy.

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice.

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8 T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction.

Crizotinib-induced immunogenic cell death in non-small cell lung cancer.

Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulates antitumor immune responses. Here we unravel the results of an unbiased screen identifying high-dose (10 µM) crizotinib as an ICD-inducing tyrosine kinase inhibitor that has exceptional antineoplastic activity when combined with non-ICD inducing chemotherapeutics like cisplatin. The combination of cisplatin and high-dose crizotinib induces ICD in non-small cell lung carcinoma (NSCLC) cells and effectively controls the growth of distinct (transplantable, carcinogen- or oncogene induced) orthotopic NSCLC models.

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy.

The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate.

TumGrowth: An open-access web tool for the statistical analysis of tumor growth curves.

The analysis of tumor growth curves is standard practice in experimental oncology including tumor immunology. In experimental oncology, cancer cells are inoculated into rodents (mostly mice) and their growth is monitored by measuring tumor diameter, surface or volume over time as a function of distinct treatments. Then, different groups of tumors/treatments are compared among each other for their evolution and possible responses to treatment.

Organs on chip approach: a tool to evaluate cancer -immune cells interactions.

In this paper we discuss the applicability of numerical descriptors and statistical physics concepts to characterize complex biological systems observed at microscopic level through organ on chip approach. To this end, we employ data collected on a microfluidic platform in which leukocytes can move through suitably built channels toward their target. Leukocyte behavior is recorded by standard time lapse imaging.

The ratio of CD8/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma .

In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8 cytotoxic T lymphocytes and FOXP3 regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8 infiltrate and the CD8/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma).

Trial Watch: Immunotherapy plus radiation therapy for oncological indications.

Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects.

Autophagy induction for the treatment of cancer.

Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e.

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy.

Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo.