Markers selectively deregulated in tumor-infiltrating regulatory t cells

Abstract

The present invention discloses a number of markers selectively deregulated in tumor-infiltrating regulatory T cells. The invention relates to molecules able to modulate the expression and/or function of at least one such marker for use in the prevention and/or treatment of the tumor. Preferably the molecule specifically binds to the marker and induces antibody-dependent cell-mediated cytotoxicity (ADCC). The invention further relates to a molecule able to modulate the expression and/or function of at least one such marker for use in a method for in vivo depleting tumor-infiltrating regulatory T cell in a subject, or for use in a method to enhance tumor immunity in a subject. Corresponding pharmaceutical compositions are also contemplated.

1 .- 26 . (canceled) 
     
     
         27 . A molecule able to modulate the expression and/or function of at least one marker that is selectively deregulated in tumor-infiltrating regulatory T cells, characterized in that:
 i) the marker is selected from the group consisting of: LAYN, MAGEH1, CCR8 and other proteins with upregulated expression in tumor-infiltrating Treg cells, including BATF, CD30, IL-1RT, IL-21R, PDL-1, PDL-2, LY75, CD177, SIRPG and CD7;   ii) the molecule targets a solid tumour selected from the group consisting of: non-small cell lung cancer, colorectal cancer, breast cancer, and gastric cancer or a metastatic cancer derived therefrom; and   iii) the molecule is for use in the prevention and/or treatment of said tumor.   
     
     
         28 . A molecule as claimed in  claim 27 , wherein the metastatic cancer is a bone, brain, or liver metastasis. 
     
     
         29 . A molecule as claimed in  claim 27  for use in the treatment of non-small cell lung cancer. 
     
     
         30 . A molecule as claimed in  claim 27  for use in the treatment of colorectal cancer. 
     
     
         31 . A molecule as claimed in  claim 27 , wherein the molecule is:
 a) an antibody or a fragment thereof;   b) a polypeptide;   c) a small molecule;   d) a polynucleotide coding for said antibody or fragment thereof or said polypeptide;   e) a polynucleotide, which is an antisense construct, antisense oligonucleotide, RNA interference construct or siRNA;   f) a vector comprising or expressing the polynucleotide as defined in d) or e); or   g) a host cell genetically engineered expressing said antibody or fragment thereof or polypeptide as defined in a) or b) or comprising the polynucleotide as defined in d) or e).   
     
     
         32 . A molecule as claimed in  claim 31 , wherein the molecule is:
 a) an antibody or fragment thereof,   d) a polynucleotide coding for said antibody or a fragment thereof; or   g) a host cell genetically engineered expressing said antibody or fragment thereof as defined in a) or comprising the polynucleotide as defined in d).   
     
     
         33 . A molecule as claimed in  claim 27 , wherein the marker has a sequence as defined by ENSEMBL_release 87 reference:
 ENSG00000204381 (LAYN);   ENSG00000179934 (CCR8); or   ENSG00000187210 (MAGEH1).   
     
     
         34 . A molecule as claimed in  claim 33 , wherein the marker has one of a sequence LAYN (SEQ ID NOs:1-9), CCR8 (SEQ ID NOs:10-11) or MAGEH1 (SEQ ID NOs: 708 or 709). 
     
     
         35 . A molecule as claimed in  claim 27 , which is iii) for use in depleting tumor-infiltrating regulatory T cells. 
     
     
         36 . A molecule as claimed in  claim 27 , which is iii) for use in enhancing tumor immunity. 
     
     
         37 . A pharmaceutical composition comprising a molecule as claimed in  claim 27  and at least one pharmaceutically acceptable carrier. 
     
     
         38 . A pharmaceutical composition according to  claim 37 , wherein the composition further comprises a further anti-tumoral agent. 
     
     
         39 . An in vitro screening, monitoring, diagnostic or prognostic method for assessing a solid tumor selected from the group consisting of: non-small cell lung cancer, colorectal cancer, breast cancer, gastric cancer, or a metastasis derived therefrom, in a subject, the method comprising the steps of:
 a) obtaining an isolated biological sample from the subject;   b) detecting in the isolated biological sample at least one marker from the group consisting of: LAYN, MAGEH1 and CCR8;   c) comparing said marker with a control; and   d) based on the comparison determining a diagnosis or prognosis.   
     
     
         40 . A method for identifying a molecule acting as an anti-tumoral molecule, comprising the steps of:
 a) assaying candidate molecules for their binding specificity to at least one marker from the group consisting of: LAYN, MAGEH1 and CCR8;   b) selecting molecules having a specific binding specificity to the at least one marker; and   c) testing selected molecules for their capacity to inhibit proliferation and/or induce an apoptotic response in a cell system against a non-small cell lung cancer, colorectal cancer, breast cancer, gastric cancer or a metastatic cancer derived therefrom.   
     
     
         41 . A method as claimed in  claim 40  wherein step c) comprises testing for selectively depleting tumor-infiltrating regulatory T cells by inducing antibody-dependent cell-mediated cytotoxicity (ADCC).