Unique cancer associated fibroblast subsets predict response to immunotherapy

A method for treating a solid tumor in a subject, comprising

• (a) detecting in a tumor biopsy sample from the subject a cancer associated fibroblast (CAF) subset expressing:
• (1) a plurality of differentially activated proteins in a first cluster (Cluster-0) selected from the group consisting of ABCC9, ACAP1, ACKR1, ADAP2, ADGRL4, ADRA2B, AGT, AK1, AKAP13, AKNA, ALPL, ANKH, ANTXR1, ANXA1, ANXA4, APBB1IP, APOLD1, APP, ARF4, ARF5, ARHGAP15, ARHGAP30, ARHGEF19, ARID4B, ARID5B, ARL2BP, ARL4A, ARL4C, ARRDC2, ASH1L, ATF6B, ATP2B1, ATP6AP2, ATRAID, AXL, BASP1, BATF, BCL11B, BCL2L11, BTG1, BTG2, C18orf32, C2orf88, C3AR1, CADM1, CALML5, CAMLG, CAPN2, CAPNS2, CAPS, CBLB, CCL4L2, CCL5, CCNH, CCR6, CCR7, CD1C, CD2, CD24, CD247, CD27, CD3D, CD3E, CD3G, CD48, CD5, CD53, CD7, CD74, CD8A, CD8B, CD9, CD96, CD99, CDC42BPA, CDC42EP3, CDH11, CDKN2A, CDKN2B, CEACAM6, CEBPB, CERCAM, CFB, CHD9, CLEC10A, CLEC4A, CLMP, CLU, CNIH1, CNKSR3, COLEC12, CORO1A, CPE, CPM, CPNE7, CRABP2, CREB3L1, CREB3L2, CREM, CRYAB, CSDE1, CSF2RA, CTLA4, CTNNB1, CTSH, CTSZ, CXCR3, CXCR4, CXCR6, CYBRD1, DAP, DAPP1, DDAH2, DDIT4, DDR2, DDX5, DERL3, DLX5, DNAJB6, DPYSL3, DSG1, DST, DTHD1, DUSP1, DUSP2, DUSP4, EBF1, EEF1D, EID1, EIF5, ELF1, EMP1, EMP2, EMP3, ENAH, ENPP2, EPB41, EPB41L2, EPHB2, ESD, ETS1, ETV3, EVI2A, EVL, EZR, F2RL3, FAP, FBXW7, FCER1A, FCER1G, FCGR2B, FGF7, FGFR1, FGFR2, FHL1, FNBP1, FNDC4, FOSL2, FOXC1, FOXC2, FOXO3, FPR1, FXYD6, FYN, FZD1, GAS1, GATA2, GDI2, GJA1, GLIPR1, GNAS, GNG7, GPBP1, GPC1, GPR132, GPR157, GPR171, GPR183, GPR65, GRAP2, GRIN2A, GSN, GSPT1, GZMA, GZMB, HCST, HDAC7, HDLBP, HERPUD1, HEXIM1, HLA-B, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-E, HNRNPDL, HOXB2, HPGD, HSPG2, HYAL2, ICOS, ID2, ID3, IFI16, IFITM2, IFNG, IKZF1, IKZF3, IL10RA, IL2RA, IL2RB, IL2RG, IL6ST, INPP5D, INTS6, ITGA10, ITGA11, ITGA4, ITGB1BP1, ITGB2, ITGB5, ITGBL1, ITM2B, ITM2C, JADE1, JAML, JMJD1C, JUN, JUNB, KCNMA1, KIR2DL4, KLF2, KLF9, KLRB1, KLRC1, KLRC2, KLRD1, LAX1, LBH, LCK, LCP1, LGALS3, LIFR, LPAR2, LPL, LRP1, LSP1, LTB, LY86, LY96, MAFB, MAGED1, MAPK13, MARCO, MARVELD1, MEF2C, MEOX2, MGST3, MKX, MMP2, MORF4L1, MS4A6A, MTUS1, MYADM, MYC, NDFIP1, NDN, NDRG2, NEO1, NET1, NFIX, NOTCH2, NOTCH4, NR3C1, NR4A3, NRP2, NSG1, NTRK3, NUDT4, PALLD, PASK, PBX1, PDCD1, PDCD4, PDE4B, PDGFC, PDGFRA, PEBP1, PFDN5, PIK3IP1, PIK3R1, PINK1, PITX1, PLEKHO1, PLSCR4, PNRC1, PPIC, PPP1R10, PPP1R2, PPP2R5C, PRDX4, PRF1, PRMT2, PRRX1, PRSS27, PSCA, PSIP1, PTGIS, PTH1R, PTN, PTP4A2, PTPRC, PTPRD, RAB30, RAB31, RAB32, RAB33A, RABAC1, RAMP2, RAMP3, RAP1B, RASGEF1B, RASGRP1, RASSF4, RASSF5, RASSF7, RBM38, RBPJ, REL, RERG, RGL4, RGS1, RGS10, RGS3, RHOD, RHOF, RHOH, RHOJ, RIPK2, RORA, RPS27L, RPSA, RRBP1, RUNX2, RUNX3, S100A10, S100A6, S1PR3, S1PR4, SAP18, SDC1, SDC2, SDCBP, SELP, SEMA7A, SERBP1, SFPQ, SH2D1A, SH2D2A, SH3BGRL, SH3BP5, SH3KBP1, SIT1, SKAP1, SKAP2, SKIL, SLA, SLA2, SLC29A1, SLC38A5, SLC41A2, SLC44A1, SLC7A5, SLCO2A1, SMAP2, SMOC1, SMOC2, SOCS1, SOD1, SOX18, SP100, SPIB, SPOCK2, SPRED1, SRSF2, STAB1, STEAP4, STK17B, STK4, STX11, STXBP6, SVIP, SYTL3, TANK, TBC1D10C, TCEA3, TCEAL2, TCEAL4, TERF2IP, TGFB1I1, TGFBI, THY1, TLE4, TMEM204, TMEM59, TNFAIP8L3, TNFRSF18, TNFSF12, TOB1, TRAF1, TRAT1, TRIM22, TSC22D3, TSHZ2, TSPAN4, TSPO, TWIST1, TXNIP, TYROBP, UBC, UBE2B, UNC5C, UTRN, VAMP2, VASN, VASP, VCAM1, VOPP1, VPS37B, WASF2, WSB1, WWTR1, YWHAQ, ZBTB16, ZBTB20, ZEB1, ZFAND5, ZFHX3, ZFHX4, ZFP36L2, ZNF106, ZNF296, and ZNF428;
• and/or
• (2) a plurality of differentially activated proteins in a second cluster (Cluster-3) selected from the group consisting of ABL2, ACAP11, ACHE1, ACKR3, ACKR41, ACTB1, ACTG1, ACTN11, ADAM12, ADD3, ADM1, ADRB21, AES1, AGPAT21, AGTRAP1, AHNAK21, AKAP131, ANGPT21, ANGPTL41, ANKRD112, ANKRD12, ANTXR11, ANXA5, AP2B11, AP2M1, AP2S1, AP3S1, APBA2, APOE1, AQP91, ARC1, ARF11, ARF41, ARHGAP152, ARNTL21, ARPC21, ASH1L1, ATP1B1, ATP2B11, ATP6AP21, ATP6V1G11, AVPR1A1, AXL1, B2M1, B4GALT1, BASP11, BATF1, BATF3, BAX1, BDKRB11, BHLHE401, BIRC31, BMP21, BSG1, BST21, BZW11, C18orf321, C31, C5AR11, CALD11, CALM2, CALM3, CALR1, CAP11, CASP11, CAV11, CAV21, CBFA2T31, CBX31, CCL21, CCL4L21, CCL8, CCR62, CCRL21, CD1641, CD1771, CD1E1, CD2741, CD300E1, CD402, CD441, CD471, CD51, CD591, CD63, CD79A2, CD82, CD831, CDC421, CDC42SE1, CEMIP, CERCAM1, CFL11, CFLAR, CHD31, CHIC2, CHMP4A, CHMP51, CHN11, CHP1, CHST11, CKS2, CLEC2B1, CLEC5A, CLEC7A1, CLIC11, CLIC4, CNIH41, CPNE11, CRABP21, CREB3L11, CSF2RA1, CSF2RB1, CSNK2B2, CTNNAL11, CXCL101, CXCL21, CXCL3, CYBA, DDR21, DIO21, DLL11, DNAJB61, DPP4, DRAP11, DUSP61, ECM1, EDF1, EDNRA1, EDNRB1, EFNA1, EHD11, EID3, EMP11, ENG1, ENO11, ENTPD11, ENY2, EREG1, ERO1A1, ETS22, ETV31, EVA1A, F2R, F2RL21, F2RL31, F31, FAP1, FCER1A2, FCER1G1, FCGR1B2, FKBP8, FLNA1, FLT31, FOSL21, FOXP1, FOXS11, FPR12, FRMD61, FST1, FSTL11, GABARAP, GAPDH1, GEM1, GGT51, GLIPR11, GNAI1, GNB11, GNG11, GNG2, GNG51, GPBP11, GPM6B1, GPR1571, GPR1831, GPX11, GREM1, GRK5, GRN1, GYPC1, HBEGF1, HCAR22, HCAR32, HES42, HIF1A, HINT11, HIVEP3, HLA-A1, HLA-B1, HLA-C1, HLA-F1, HM13, HPGD1, HRAS, HSBP11, HSPA51, ICAM11, IFI271, IFI61, IFITM11, IFITM21, IFITM31, IFNGR11, IGF2, IGFBP31, IGFBP61, IGFLR11, IL10, IL11, IL15RA1, IL1A1, IL1B1, IL1R1, IL1R22, IL1RAP1, IL2RA1, IL2RG1, IL61, IL7R, ILK1, INHBA, INSIG11, IRF41, IRF7, ITGA1, ITGA5, ITGAV, ITGB1, ITGB42, ITGB61, ITSN22, KCNJ81, KCNK61, KIR2DL41, KLF61, KLRB11, KLRC11, LAMP5, LCP21, LGALS1, LGALS3BP1, LGALS9, LHX81, LILRA11, LILRB21, LIMA11, LIMS11, LMCD1, LMO41, LOXL2, LPXN, LRRFIP11, LSR2, LTB1, LY6E1, LY6K, LYPD11, MAP1B1, MAP3K81, MARCKS1, MARCKSL1, MGST21, MIF1, MMP14, MORF4L2, MSC, MSN1, MSX2, MX1, MXD11, MYADM2, MYH9, MYO101, MYO1G1, NACC1, NAMPT1, NCOA71, NDUFA131, NEDD41, NEDD81, NEO11, NET12, NFE2L3, NFKB11, NGFR1, NLRP31, NME21, NOTCH31, NRG11, NRP11, NTM1, OLR11, PAG1, PALLD1, PARK72, PARP14, PDGFRB1, PDIA31, PDIA61, PDLIM11, PDPN, PFDN51, PFN11, PHLDA1, PILRA1, PIM21, PKIG1, PKM1, PLAT1, PLAU, PLAUR, PLEC2, PLEK1, PLK2, PLP22, PLPP32, PLPP4, PLSCR11, PLXDC11, PMAIP1, PMEPA1, POLR2L1, PON2, PPIC1, PPP1R21, PRCP1, PRDM1, PRDX41, PRKAR1A1, PRMT11, PROCR2, PRRX11, PRRX2, PSMA4, PTEN, PTGER3, PTGES, PTGIR, PTHLH, PTK7, PTPN11, PTPRE1, PTTG11, RAB101, RAB131, RAB1A, RAB301, RAB311, RAB321, RAB33A1, RAB5C1, RABAC11, RANBP11, RAP1A, RAP1B1, RASD1, RASGEF1B1, RBPJ1, RBPMS, REL2, RGL41, RGS161, RGS2, RGS31, RGS4, RHEB2, RHOBTB11, RHOC, RHOF1, RHOG2, RHOH1, RIN2, RIPK21, RND31, RPS27L1, RRAD1, RRBP11, S100A111, S100A121, S100A16, S100A61, SCAND11, SCG5, SDC11, SDC41, SECTM12, SELE1, SERPINB9, SERPINE12, SGIP11, SGK11, SHISA51, SIGLEC102, SKIL1, SLA21, SLC1A51, SLC24A41, SLC2A31, SLC2A6, SLC39A14, SLC3A21, SLC41A21, SLC7A111, SLC7A51, SLC9A3R22, SNA121, SOD21, SOX11, SOX4, SQSTM11, STAT11, STAT2, STEAP1, STEAP21, STX111, SUB11, SULF1, SULF21, SYTL21, TANK1, TAX1BP31, TCF41, TFP11, TGFB1I11, TGFB31, TGIF1, THBD1, THBS11, THY11, TLR21, TMEM2041, TNF1, TNFAIP31, TNFAIP61, TNFRSF12A1, TNFRSF1A, TNFRSF1B1, TNFRSF21, TNFSF101, TNFSF13B2, TNFSF141, TRAF11, TREM11, TRIB11, TRIM221, TSC22D11, TSPAN151, TSPAN9, TWIST11, TWIST2, TXNDC171, UACA1, UBB1, UBE2B1, UBE2D31, UBE2L31, VAMP21, VAMP51, VAMP82, VASP2, VCAM11, VDAC11, VEGFA1, WNT2, WNT5A, XBP11, YWHAH1, ZNF2671, ZNF2962, ZNF469, ZNF503, and ZNHIT11;
• and
• (b) treating the subject with an immunotherapy.

A method for treating a solid tumor in a subject, comprising

• (a) isolating cancer associated fibroblasts (CAFs) from the subject,
• (b) isolating and expanding a subset of the CAFs that differentially express:
• (1) a plurality of genes in a first cluster (Cluster-0) selected from the group consisting of AEBP1, ALPL, ANGPTL2, ANKH, ANKRD28, ANTXR1, APOL2, APP ASPN, B4GALT1, BAMBI, BGN, BICC1, BNIP3, C10orf10, C1orf54, CADM1, CCDC3, CCNG2, CD276, CD9, CDC42EP3, CDH11, CDKN2A, CERCAM, CITED2, CKAP4, CKB, CLEC11A, CLMP CNKSR3, COL12A1, COL16A1, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, COL6A3, COL8A1, COPZ2, CPE, CSF1, CTGF, CTHRC1, CTNNB1, CTSK, CTSZ, CXCL12, CXCL14, CYR61, DCN, DDIT4, DLX5, EDIL3, EFEMP2, EFNA5, EMILIN1, ENAH, ENPP2, ERRF1, EVI2A, FAM134B, FAP FBLN1, FBLN7, FCGRT FGFR1, FKBP10, FLRT2, FMOD, FNDC3B, FSCN1, FXYD6, GADD45G, GALNT1, GAS1, GGT5, GJA1, GLT8D2, GOLIM4, GOLM1, GPNMB, HAPLN1, HERPUD1, HES1, HSPG2, HTRA1, ID2, IGF2, IGFBP4, IGHG1, IGHG3, IGHG4, IGKC, IGLC2, IRX3, JCHAIN, KCNQ1OT1, KCTD12, KDELR3, LAMB1, LAPTM4A, LAYN, LIMCH1, LMO7, LOXL1, LPAR1, LSP1, LUM, MAFB, MAP4K4, MARCKS, MDK, MFAP2, MIR99AHG, MMP11, MMP14, MMP2, MT1E, MT1X, MT-ND3, MT-ND4, MT-ND5, MXRA5, MXRA8, MZB1, NBL1, NNMT NPC2, NR3C1, NRP2, OLFML2B, OLFML3, P3H4, PALLD, PCOLCE, PDGFC, PDGFD, PDPN, PFN2, PIK3R1, PLD3, PLEKHA5, PODNL1, POSTN, PPA1, PRRX1, PRSS23, PSAP PTPRS, QKI, RAB31, RA114, RCAN1, RCN3, RGS3, S100A10, S100A13, S100A4, SCRG1, SDC1, SDC2, SEPP1, SERPINF1, SERPINH1, SERTAD4, SESN3, SFRP2, SH3BP5, SMOC2, SNA12, SPARC, SRP14, SSPN, SSR4, STK17B, THBS2, TIMP3, TPST1, TSC22D3, UNC5B, VCAM1, VCAN, VIM, WIPF1, YPEL2, ZEB1, ZFHX4, and ZFP36L2;
• and/or
• (2) a plurality of genes in a second cluster (Cluster-3) selected from the group consisting of ACTB, ADAM121, ADAM19, ADAMTS2, AKR1B11, ALDH2, ANPEP ANXA2, ANXA5, ANXA61, APOL1, AQP1, ARID5A2, ARL4C, BASP11, BMP2, BPGM, BST21, C12orf75, CALD11, CCL21, CD2481, CD82, CEP57L1, CHMP1B1, CHPF2, COL15A1, COL1A11, COL3A11, COL5A11, COL5A21, COL5A31, COL6A1, COL6A2, COL6A31, COL7A1, CRABP2, CREB3L21, CTHRC11, CXCL11, CXCL3, CXCL81, DIXDC1, DNAJA11, EIF5A, EMILIN11, ENO1, EVA1A, F2R1, F3, FAM129B, FAM19A5, FARP11, FKBP11, FN1, FSTL11, FTH11, GAPDH, GBP1, GCNT1, GLIPR2, GLIS31, GNAI2, GOLM11, GPM6B, GREM11, GUCY1A31, H1F01, HES41, HIF1A1, HILPDA, HLA-A1, HLA-B, HLA-C, HSPA181, HSPA5, HSPH1, HTRA3, IFI271, IFI44L1, IFI61, IFIT1, IFIT31, IFITM1, IGFBP3, IL11, IL24, IL32, IL61, INHBA, IRF7, ISG151, ISLR, ITGA5, ITGAV1, KLF6, LAMA41, LGALS1, LGMN1, LINC001521, LOXL11, LOXL2, LY6E, MAGEH1, MEST METRNL, MFAP21, MFAP51, MME1, MMP1, MMP111, MMP141, MT-C02, MX1, MX21, NES1, NOX4, NREP, NTM1, OAS1, PAPPA1, PDLIM4, PFN1, PHLDA31, PKM, PLAT PLAU, PLXNC1, PMEPA1, POSTN1, PRRX21, PTGES1, PTK7, PXDN, RARRES2, RIN2, RORA1, RP11-115D19.1, RP3-325F22.5, S100A11, S100A16, S100A61, SAT1, SCG5, SCX, SEC23A, SELM, SERINC2, SERPINE1, SERPINH11, SGK1, SPON2, STC2, STEAP11, SUGCT SULF1, TAGLN1, TCTN3, TGFBI, TGM2, TIMP2, TMEM158, TMEM45A, TMSB10, TNC, TNFAIP61, TNFRSF12A1, TPM11, TPM21, TRIOBP TUBA1A, TUBA1C, TWIST21, TYMP VCAN1, WARS, WDFY1, WIPI11, WNT5A1, XAF1, ZFAND2A, and ZMPSTE24;
• and
• (c) administering the expanded CAF subset to the subject in combination with an immunotherapy.