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WO 2017/055322 Al O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/055322 Al 6 April 2017 (06.04.2017) W P O PCT (51) International Patent Classification: Umrsl l38, Equipe 13, 15 rue de l'Ecole de Medecine, C12Q 1/68 (2006.01) 75006 Paris (FR). (21) International Application Number: (74) Agent: COLLIN, Matthieu; Inserm Transfert 7 rue Watt, PCT/EP2016/073053 75013 Paris (FR). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 28 September 2016 (28.09.201 6) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (25) Filing Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (26) Publication Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (30) Priority Data: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, EP15306521.4 29 September 2015 (29.09.2015) EP MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, EP16305886.0 12 July 2016 (12.07.2016) EP OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (71) Applicants: INSERM (INSTITUT NATIONAL DE LA SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, SANTE ET DE LA RECHERCHE MEDICALE) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, [FR/FR]; 101, rue de Tolbiac, 75013 Paris (FR). UNI¬ ZW. VERSITE PARIS DIDEROT - PARIS 7 [FR/FR]; 5, rue (84) Designated States (unless otherwise indicated, for every Thomas Mann, 75013 Paris (FR). UNIVERSITE kind of regional protection available): ARIPO (BW, GH, PIERRE ET MARIE CURIE (PARIS 6) [FR/FR]; 4, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, place Jussieu, 75005 Paris (FR). UNIVERSITE PARIS TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, DESCARTES [FR/FR]; 12, rue de l'Ecole de Medecine, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 75006 Paris (FR). LIGUE NATIONALE CONTRE LE DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, CANCER [FR/FR]; 14 rue Corvisart, 7501 3 Paris (FR). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, ASSISTANCE PUBLIQUE-HOPITAUX DE PARIS SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (APHP) [FR/FR]; 3, avenue Victoria, 75004 Paris (FR). GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: FRD3MAN, Wolf Herman; Centre de Recher Published: che les Cordeliers / Inserm U 1138, 15 rue de l'Ecole de — with international search report (Art. 21(3)) Medecine, 75270 Paris (FR). DE REYNIES, Aurelien; Ligue Nationale Contre le Cancer, Programme CIT, 14 rue Corvisart, 75013 Paris (FR). BECHT, Etienne; Inserm © o- (54) Title: METHODS FOR QUANTIFYING THE POPULATION OF NEUTROPHILS IN A TISSUE SAMPLE (57) Abstract: The present invention relates to methods for quantifying the population of neutrophils in a tissue sample. In particu- lar, the present invention relates to a method for quantifying the population of neutrophils in a tissue sample obtained from a subject comprising determining the expression level of at least one gene selected from the group consisting of CXCR2, VNN3, CYP4F3, HAL, GENE 1, FCGR3B, KCNJ15, CXCR1, STEAP4 and TNFRSF10C. METHODS FOR QUANTIFYING THE POPULATION OF NEUTROPHILS IN A TISSUE SAMPLE FIELD OF THE INVENTION: The present invention relates to methods for quantifying the population of neutrophils in a tissue sample. BACKGROUND OF THE INVENTION: Tumors grow within a microenvironment composed of immune cells, endothelial cells, fibroblasts and adjacent normal tissue. The composition of the tumor microenvironment is of paramount importance during tumor development. Notably, infiltration by cells of the adaptive immune system helps control tumor growth and correlate with a favorable clinical outcome in most cancers. A consensual result is that infiltration with memory CD8+ T cells is associated with a favorable patient's outcome. However, there are exceptions to this rule. Notably, in clear cell renal cell carcinoma (ccRCC), where angiogenesis is highly due to mutations disrupting the HIF pathway regulating the cellular response to hypoxia, tumor-infiltration by CD8+ T cells is associated with a poor prognosis for the patient. To understand this surprising result, the inventors recently performed a comprehensive characterization of the microenvironmental components associated to CD8+ T cells' infiltration in ccRCC. It appeared that in this malignancy, CD8+ T cells infiltration is associated with a strong infiltration by other immune cells, including B cells and cells of monocytic origin. Conversely, in colorectal cancer (CRC), it is well known that infiltration by CD8+ T cells is associated with a favorable outcome. This disease is also highly heterogeneous in terms of tumor-cell phenotypes, as up to six molecular subgroups have been described, which differ in carcinogenesis pathways, methylation profile, DNA mutational burden, and prognosis. The subgroup with the best prognosis featured a strong infiltration by cytotoxic lymphocytes. Surprisingly, the worst-prognosis subgroup also displayed a strong immune infiltration, with intermediate expression of lymphocytes' markers and a strong myeloid component, as well as a high signature of endothelial cells and fibroblasts. Further analysis revealed an increased expression of pro-inflammatory and pro-angiogenic molecules in this subgroup, which appear to originate from microenvironment's fibroblasts. Altogether, these data underline the importance of a full characterization of the immune, endothelial and fibroblastic components of the microenvironment to decipher interactions between these cell types and deliver therapies aimed at orienting inflammatory microenvironments towards a more immuneresponsive state. SUMMARY OF THE INVENTION: The present invention relates to methods for quantifying the population of neutrophils in a tissue sample. In particular, the present invention is defined by the claims. DETAILED DESCRIPTION OF THE INVENTION: The tumor microenvironment is a complex tissue which contains many distinct cell populations, and whose composition may predict prognosis and response to therapies. In the present disclosure, using samples of purified cell populations, the inventors defined specific and robust transcriptomic markers of the immune and stromal cell populations of the tumor microenvironment, and they quantitatively validated them in an in-vitro R A mixture model. For this purpose, they developed the 'Microenvironment Cell Populations-counter' (MCP-counter) method, which, using transcriptomic data, allows a robust quantification of the abundance of immune and stromal populations in cellularly heterogeneous tissues. They present in-vitro and ex-vivo data supporting the validity of this method's estimates and they apply MCP-counter to draw a global picture of immune infiltrates across human healthy tissues and non-hematopoietic tumors, and to confirm recently-identified microenvironment-based cancer stratifications associated with overall-survival in lung adenocarcinoma, colorectal, and breast cancers. Accordingly a first object of the present invention relates to a method for quantifying the population of neutrophils in a tissue sample obtained from a subject comprising determining the expression level of at least one gene selected from the group consisting of CXCR2, VNN3, CYP4F3, HAL, GENE 1, FCGR3B, KCNJ15, CXCR1, STEAP4 and TNFRSF10C wherein the determined expression level indicates the quantity of the population of neutrophils in the tissue sample. As used herein, the term "neutrophils" also known as "granulocytes" has its general meaning in the art. Neutrophils are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes (PMN, PML, or PMNL) because of the varying shapes of the nucleus, which is usually lobed into three segments. This distinguishes them from the mononuclear agranulocytes. In common parlance, the term polymorphonuclear leukocyte often refers specifically to neutrophil granulocytes, the most abundant of the granulocytes; the other types (eosinophils, basophils, and mast cells) have lower numbers. Neutrophils are produced via granulopoiesis in the bone marrow. As used herein, the term "subject" denotes a mammal such as a rodent, a feline, a canine and a primate. Preferably, a subject according to the invention is a human. As used herein, the term "tissue", when used in reference to a part of a body or of an organ, generally refers to an aggregation or collection of morphologically similar cells and associated accessory and support cells and intercellular matter, including extracellular matrix material, vascular supply, and fluids, acting together to perform specific functions in the body. There are generally four basic types of tissue in animals and humans including muscle, nerve, epithelial, and connective tissues. In some embodiments, when the subject suffers from a cancer, the tissue sample is a tumor tissue sample. As used herein, the term "tumor tissue sample" means any tissue tumor sample derived from the patient. Said tissue sample is obtained for the purpose of the in vitro evaluation. In some embodiments, the tumor sample may result from the tumor resected from the patient. In some embodiments, the tumor sample may result from a biopsy performed in the primary tumour of the patient or performed in metastatic sample distant from the primary tumor of the patient. In some embodiments, the tumor tissue sample encompasses a global primary tumor (as a whole), a tissue sample from the center of the tumor, a tumor tissue sample collected prior surgery (for follow-up of patients after treatment for example), and a distant metastasis. The tumor tissue sample can, of course, be subjected to a variety of well-known post-collection preparative and storage techniques (e.g., fixation, storage, freezing, etc.). The sample can be fresh, frozen, fixed (e.g., formalin fixed), or embedded (e.g., paraffin embedded.
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