Monocyte modulation and control of tumor metastasis

Abstract

Disclosed herein are methods of increasing numbers of monocytes to a tumor or cancer metastasis site in a subject. Non-limiting embodiments include administering or using a Nur77 polypeptide or subsequence thereof; a Nur77 agonist; a CX3CR1 agonist; CD14+CD16+ monocytes and/or CD14dimCD16+ (CD115+CD11b+GR1− (Ly6C−)) monocytes; CD14+CD16+ monocytes and/or CD14dimCD16+ (CD115+CD11b+GR1− (Ly6C−)) monocytes contacted with a Nur77 agonist or contacted with a CX3CR1 agonist. Also disclosed herein are methods of increasing, stimulating, activating or promoting monocyte migration to or mobilization against a tumor or cancer metastasis in a subject. Non-limiting embodiments include administering a Nur77 polypeptide or subsequence thereof; a Nur77 agonist; a CX3CR1 agonist; CD14+CD16+ monocytes and/or CD14dimCD16+ (CD115+CD11b+GR1− (Ly6C−)) monocytes; or CD14+CD16+ monocytes and/or CD14dimCD16+ (CD115+CD111b+GR1− (Ly6C−)) monocytes contacted with a Nur77 agonist or contacted with a CX3CR1 agonist.

What is claimed is: 
     
         1 . A method of increasing numbers of monocytes to a tumor or cancer metastasis site in a subject comprising administering a
 (a) Nur77 polypeptide or subsequence thereof;   (b) Nur77 agonist;   (c) CX3CR1 agonist;   (d) CD14 + CD16 +  monocytes and/or CD14 dim CD16 +  (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes; or   (e) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with a Nur77 agonist or contacted with a CX3CR1 agonist, to a subject in an amount that increases numbers of monocytes in the tumor or cancer metastasis site.   
     
     
         2 . A method of increasing, stimulating, activating or promoting monocyte migration to or mobilization against a tumor or cancer metastasis in a subject comprising administering a
 (a) Nur77 polypeptide or subsequence thereof;   (b) Nur77 agonist;   (c) CX3CR1 agonist;   (d) CD14 + CD16 +  monocytes and/or CD14 dim CD16 +  (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes; or   (e) CD14 + CD16 +  monocytes and/or CD14 dim CD16 +  (CD115 + CD11b + GR1 − (Ly6C−)) monocytes contacted with a Nur77 agonist or contacted with a CX3CR1 agonist, to a subject in an amount that increases, stimulates, activates or promotes monocyte migration to or mobilization against the tumor or cancer metastasis.   
     
     
         3 . A method of controlling, limiting, or decreasing metastasis of a tumor or cancer in a subject, comprising administering a
 (a) Nur77 polypeptide or subsequence thereof;   (b) Nur77 agonist;   (c) CX3CR1 agonist;   (d) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes; or   (e) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with a Nur77 agonist or contacted with a CX3CR1 agonist, to a subject in an amount to control, limit, or decrease metastasis of the tumor or cancer in the subject.   
     
     
         4 . A method of controlling, limiting, or decreasing metastasis of a tumor or cancer from an original site to one or more other sites in a subject, comprising administering a
 (a) Nur77 polypeptide or subsequence thereof;   (b) Nur77 agonist;   (c) CX3CR1 agonist;   (d) CD14 + CD16 +  monocytes and/or CD14 dim CD16 +  (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes; or   (e) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with a Nur77 agonist or contacted with a CX3CR1 agonist, to a subject in an amount to control, limit, or decrease metastasis of the tumor or cancer in the subject.   
     
     
         5 . A method of controlling, limiting, or decreasing metastasis of a tumor or cancer in a subject, comprising administering a
 (a) CX3CR1 agonist;   (b) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes; or   (c) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with a CX3CR1 agonist,   to a subject in an amount to control, limit, or decrease metastasis of the tumor or cancer in the subject.   
     
     
         6 . A method of controlling, limiting, or decreasing metastasis of a tumor or cancer from an original site to one or more other sites in a subject, comprising administering a
 (a) Nur77 polypeptide or subsequence thereof;   (b) Nur77 agonist;   (c) CX3CR1 agonist;   (d) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes; or   (e) CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with a Nur77 agonist or contacted with a CX3CR1 agonist, to a subject in an amount to control, limit, or decrease metastasis of the tumor or cancer in the subject.   
     
     
         7 . The method of any of  claims 1 - 6 , wherein the method decreases, reduces, inhibits, suppresses, limits or controls metastasis of the cancer or tumor, or decreases, reduces, inhibits, suppresses, limits or controls establishment of a tumor or cancer metastasis at one or more sites other than the original site of the tumor or cancer in the subject. 
     
     
         8 . The method of any of  claims 1 - 6 , wherein the method decreases, reduces, inhibits, suppresses, limits or controls growth or proliferation of a tumor or cancer metastasis at one or more sites other than the original site of the tumor or cancer in the subject. 
     
     
         9 . The method of any of  claims 1 - 6 , wherein the method decreases or reduces tumor or cancer metastasis at one or more sites other than the original site of the tumor or cancer in the subject. 
     
     
         10 . The method of any of  claims 1 - 6 , wherein the tumor or cancer metastasis is in a lung in the subject. 
     
     
         11 . The method of any of  claims 1 - 6 , wherein the site(s) other than the original site of the tumor or cancer is a lung. 
     
     
         12 . The method of any of  claims 1 - 6 , wherein the method stimulates, promotes, increases or induces CD14 + CD16 +  or CD14 dim  CD16 +  monocyte cell production, development, survival, proliferation, differentiation or activity. 
     
     
         13 . The method of any of  claims 1 - 12 , wherein the subject is in need of treatment for a tumor or cancer. 
     
     
         14 . The method of any of  claims 1 - 12 , wherein the subject has been treated or is in remission from a tumor or cancer. 
     
     
         15 . The method of any of  claims 1 - 4  or  6 - 12 , wherein the Nur77 polypeptide or subsequence thereof comprises a subsequence of full length Nur77 polypeptide. 
     
     
         16 . The method of any of  claims 1 - 4  or  6 - 12 , wherein the Nur77 polypeptide, subsequence thereof, or Nur77 agonist is mammalian. 
     
     
         17 . The method of any of  claims 1 - 4  or  6 - 12 , wherein the Nur77 polypeptide, subsequence thereof or Nur77 agonist is human. 
     
     
         18 . The method of any of  claims 1 - 4  or  6 - 12 , wherein the Nur77 polypeptide or subsequence thereof comprises full length or a subsequence of a human protein sequence or a polymorphism thereof set forth as: 
       
         
           
                 
               
                   Human NR4A1 protein sequence ( Homo sapiens  nuclear 
                 
                   receptor subfamily 4, group A, member 1 (NR4A1):  
                 
                   MWLAKACWSIQSEMPCIQAQYGTPAPSPGPRDHLASDPLTPEFIKPTMDL 
                 
                     
                 
                   ASPEAAPAAPTALPSFSTFMDGYTGEFDTFLYQLPGTVQPCSSASSSASS 
                 
                     
                 
                   TSSSSATSPASASFKFEDFQVYGCYPGPLSGPVDEALSSSGSDYYGSPCS 
                 
                     
                 
                   APSPSTPSFQPPQLSPWDGSFGHFSPSQTYEGLRAWTEQLPKASGPPQPP 
                 
                     
                 
                   AFFSFSPPTGPSPSLAQSPLKLFPSQATHQLGEGESYSMPTAFPGLAPTS 
                 
                     
                 
                   PHLEGSGILDTPVTSTKARSGAPGGSEGRCAVCGDNASCQHYGVRTCEGC 
                 
                     
                 
                   KGFFKRTVQKNAKYICLANKDCPVDKRRRNRCQFCRFQKCLAVGMVKEVV 
                 
                     
                 
                   RTDSLKGRRGRLPSKPKQPPDASPANLLTSLVRAHLDSGPSTAKLDYSKF 
                 
                     
                 
                   QELVLPHFGKEDAGDVQQFYDLLSGSLEVIRKWAEKIPGFAELSPADQDL 
                 
                     
                 
                   LLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCARGFGDWIDSIL 
                 
                     
                 
                   AFSRSLHSLLVDVPAFACLSALVLITDRHGLQEPRRVEELQNRIASCLKE 
                 
                     
                 
                   HVAAVAGEPQPASCLSRLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPPI 
                 
                     
                 
                   IDKIFMDTLPF;  
                 
                   Or  
                 
                     
                 
                     Homo   sapiens  nuclear receptor subfamily 4, group  
                 
                   A, member 1 (NR4A1) 
                 
                   >NP_002126 length = 598 >NP_775180 length = 598  
                 
                   MPCIQAQYGTPAPSPGPRDHLASDPLTPEFIKPTMDLASPEAAPAAPTAL 
                 
                     
                 
                   PSFSTFMDGYTGEFDTFLYQLPGTVQPCSSASSSASSTSSSSATSPASAS 
                 
                     
                 
                   FKFEDFQVYGCYPGPLSGPVDEALSSSGSDYYGSPCSAPSPSTPSFQPPQ 
                 
                     
                 
                   LSPWDGSFGHFSPSQTYEGLRAWTEQLPKASGPPQPPAFFSFSPPTGPSP 
                 
                     
                 
                   SLAQSPLKLFPSQATHQLGEGESYSMPTAFPGLAPTSPHLEGSGILDTPV 
                 
                     
                 
                   TSTKARSGAPGGSEGRCAVCGDNASCQHYGVRTCEGCKGFFKRTVQKNAK 
                 
                     
                 
                   YICLANKDCPVDKRRRNRCQFCRFQKCLAVGMVKEVVRTDSLKGRRGRLP 
                 
                     
                 
                   SKPKQPPDASPANLLTSLVRAHLDSGPSTAKLDYSKFQELVLPHFGKEDA 
                 
                     
                 
                   GDVQQFYDLLSGSLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILR 
                 
                     
                 
                   LAYRSKPGEGKLIFCSGLVLHRLQCARGFGDWIDSILAFSRSLHSLLVDV 
                 
                     
                 
                   PAFACLSALVLITDRHGLQEPRRVEELQNRIASCLKEHVAAVAGEPQPAS 
                 
                     
                 
                   CLSRLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPPIIDKIFMDTLPF;  
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a polymorphism thereof. 
       
     
     
         19 . The method of  claim 18 , wherein the polymorphism is an amino acid substitution at one or more amino acid positions 26, 36, 74, 137, 262, or 400 of Nur77. 
     
     
         20 . The method of  claim 18 , wherein the polymorphism is a change of one or more of: a (L) Leu to (V) Val at position 26; a (D) Asp to (G) Gly at position 36; a (T) Thr to (1) Ile at position 74; an (S) Ser to (L) Leu at position 137; a (G) Gly to (R) Arg at position 262; a (G) Gly to (A) Ala at position 262; or a (A) Ala to (D) Asp at position 400. 
     
     
         21 . The method of any of  claims 1 - 12 , wherein the Nur77 polypeptide, subsequence thereof, Nur77 agonist or CX3CR1 agonist comprises a fusion polypeptide, or a chimeric polypeptide. 
     
     
         22 . The method of  claim 21 , wherein the chimeric polypeptide comprises a Nur77 polypeptide, subsequence thereof, Nur77 agonist or CX3CR1 agonist fused to an immunoglobulin polypeptide. 
     
     
         23 . The method of any of  claims 1 - 12 , wherein the Nur77 agonist or CX3CR1 agonist comprises a small molecule. 
     
     
         24 . The method of any of  claims 1 - 4 ,  6 - 12  or  23 , wherein the Nur77 agonist or small molecule comprises one or more of: 9-cis-retinoic acid; 1-di(3-indolyl)-1-(4-X-phenyl)methanes; etoposide; 5,8-diacetoxyl-6-(1′-acetoxy-4′-methyl-3′-pentenyl)-1,4-naphthaquinones; 12-O-tetradecanoylphorbol-13-acetate; diindolylmethane analogs (C-DIMs); 6-mercaptopurine; panobinostat ((2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide); or octaketide Cytosporone B (Csn-B) or a derivative thereof. 
     
     
         25 . The method of  claim 24 , wherein the diindolylmethane analog (C-DIM) is 1,1-bis(3′-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH3). 
     
     
         26 . The method of  claim 24 , wherein the Cytosporone B (Csn-B) derivative is n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate or a compound having a structure set forth in Table 1. 
     
     
         27 . The method of any of  claims 1 - 12 , wherein the Nur77 polypeptide or subsequence thereof, Nur77 agonist, CX3CR1 agonist, CD14 + CD16 +  monocytes and/or CD14 dim CD16 +  (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes or CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with Nur77 agonist or contacted with CX3CR1 agonist is administered by injection, infusion, catheter, enema, intravenously, intraarterially, orally, intramuscularly, intraperitoneally, intradermally, subcutaneously, intracavity, intrarectally, intracranially, topically, transdermally, optically, parenterally, or transmucosally. 
     
     
         28 . The method of any of  claims 1 - 12 , wherein the Nur77 polypeptide or subsequence thereof, Nur77 agonist, CX3CR1 agonist, CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes or CD14 + CD16 +  monocytes and/or CD14 dim  D16 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with Nur77 agonist or contacted with CX3CR1 agonist is administered for a period of 60 minutes or less, for a period of 30 minutes or less, for a period of 15 minutes or less, or for a period of 5 minutes or less, or for a period of 1 minute or less. 
     
     
         29 . The method of any of  claims 1 - 12 , wherein the Nur77 polypeptide or subsequence thereof, Nur77 agonist, CX3CR1 agonist, CD14 + CD16 +  monocytes and/or CD14 dim CD16 (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes or CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with Nur77 agonist or contacted with CX3CR1 agonist, is administered within 12-24, 24-48, or 48-72 hours of after diagnosis of a tumor or cancer in the subject. 
     
     
         30 . The method of any of  claims 1 - 12 , wherein the Nur77 polypeptide or subsequence thereof, Nur77 agonist or CX3CR1 agonist, is administered in a range of about 100 μg/ml to 1,000 mg/ml, or in a range of 1,000 μg/ml to 500 mg/ml. 
     
     
         31 . The method of any of  claims 1 - 12 , wherein the Nur77 polypeptide or subsequence thereof, Nur77 agonist or CX3CR1 agonist, is administered in an amount of 0.1-10,000, 0.5-5,000, 1-1,000, 10-100, or 25-75 milligrams to the subject, singly or 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times. 
     
     
         32 . The method of any of  claims 1 - 12 , wherein the Nur77 polypeptide or subsequence thereof, Nur77 agonist, CX3CR1 agonist, CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes or CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with Nur77 agonist or contacted with CX3CR1 agonist, is administered in a pharmaceutically or biologically acceptable carrier. 
     
     
         33 . The method of  claim 32 , wherein the pharmaceutically acceptable carrier comprises saline. 
     
     
         34 . The method of any of  claims 1 - 12 , wherein the cancer or tumor comprises a solid cellular mass. 
     
     
         35 . The method of any of  claims 1 - 12 , wherein the cancer or tumor comprises hematopoietic cells. 
     
     
         36 . The method of any of  claims 1 - 12 , wherein the cancer or tumor comprises a carcinoma, sarcoma, lymphoma, leukemia, adenoma, adenocarcinoma, melanoma, glioma, glioblastoma, meningioma, neuroblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, mesothelioma, reticuloendothelial, lymphatic or haematopoietic cancer or tumor. 
     
     
         37 . The method of any of  claims 1 - 12 , wherein the cancer or tumor comprises a sarcoma, carcinoma, melanoma, lymphoma, leukemia, or myeloma. 
     
     
         38 . The method of  claim 37 , wherein the sarcoma comprises a lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma or fibrosarcoma. 
     
     
         39 . The method of any of  claims 1 - 12 , wherein the cancer or tumor comprises a haematopoietic cancer or tumor. 
     
     
         40 . The method of any of  claims 1 - 12 , wherein the cancer or tumor comprises a myeloma, lymphoma or leukemia. 
     
     
         41 . The method of any of  claims 1 - 12 , wherein the cancer or tumor is originally present in, or is known to metastasize to, lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid, lymph, gastrointestinal tract, mouth, esophagus, stomach, duodenum, ileum, jejunum (small intestine), colon, rectum, genito-urinary tract (uterus, ovary, cervix, endometrial, bladder, testicle, penis, prostate), kidney, pancreas, liver, bone, bone marrow, lymph, blood, muscle, skin, or biliary tract. 
     
     
         42 . The method of any of  claims 1 - 12 , wherein the cancer or tumor is originally present in, or has metastasized to, lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid, lymph, gastrointestinal tract, mouth, esophagus, stomach, duodenum, ileum, jejunum (small intestine), colon, rectum, genito-urinary tract (uterus, ovary, cervix, endometrial, bladder, testicle, penis, prostate), kidney, pancreas, liver, bone, bone marrow, lymph, blood, muscle, skin, or biliary tract. 
     
     
         43 . The method of  claim 41  or  42 , wherein the lung cancer or tumor comprises small cell lung or non-small cell lung cancer. 
     
     
         44 . The method of any of  claims 1 - 12 , wherein the Nur77 agonist or the CX3CR1 agonist comprises an antibody or an antibody fragment. 
     
     
         45 . The method of  claim 44 , wherein said antibody fragment comprises an Fab, Fab′, F(ab′) 2 , Fv, Fd, single-chain Fv (scFv), disulfide-linked Fvs (sdFv), V L , V H , Camel Ig, V-NAR, VHH, trispecific (Fab 3 ), bispecific (Fab 2 ), diabody ((V L —V H ) 2  or (V H —V L ) 2 ), triabody (trivalent), tetrabody (tetravalent), minibody ((scF V -C H 3) 2 ), bispecific single-chain Fv (Bis-scFv), IgGdeltaCH2, scFv-Fc, (scFv) 2 -Fc, affibody, aptamer, avimer or nanobody. 
     
     
         46 . The method of  claim 44 , wherein said antibody comprises a mammalian antibody. 
     
     
         47 . The method of  claim 44 , wherein said antibody comprises a human, humanized, primatized, or chimeric antibody. 
     
     
         48 . The method of any of  claims 1 - 12 , further comprising administering an anti-cell proliferative, anti-neoplastic, anti-tumor, anti-cancer or immune-enhancing treatment or therapy. 
     
     
         49 . The method of  claim 48 , wherein the treatment or therapy comprises surgical resection, radiotherapy, ionizing or chemical radiation therapy, chemotherapy, immunotherapy, local or regional thermal (hyperthermia) therapy, or vaccination. 
     
     
         50 . The method of  claim 48 , wherein the Nur77 polypeptide or subsequence thereof, Nur77 agonist, CX3CR1 agonist, CD14 + CD16 +  monocytes and/or CD14 dim CD16 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes or CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with Nur77 agonist or contacted with CX3CR1 agonist is administered prior to, substantially contemporaneously with or following administration of the anti-cell proliferative, anti-neoplastic, anti-tumor, anti-cancer or immune-enhancing treatment or therapy. 
     
     
         51 . The method of any of  claims 1 - 50 , wherein the subject is a mammal. 
     
     
         52 . The method of any of  claims 1 - 50 , wherein the subject is a human. 
     
     
         53 . A pharmaceutical composition comprising a Nur77 polypeptide or subsequence thereof, a Nur77 agonist, a CX3CR1 agonist, CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes or CD14 + CD16 +  monocytes and/or CD14 dim CD6 + (CD115 + CD11b + GR1 −  (Ly6C−)) monocytes contacted with Nur77 agonist or contacted with CX3CR1 agonist.