Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer

A method of detecting an immune checkpoint inhibitor resistance (ICR) gene signature in a tumor comprising detecting in tumor cells obtained from a subject in need thereof the expression or activity of:

• a malignant cell gene signature comprising:
• a) one or more genes or polypeptides selected from the group consisting of PPIA, RPL31, RPL37A, RPL41, RPS21, RPS27A, SAE1, UBA52, C19orf48, CHCHD2, FARSA, NONO, RPL27, RPL36, RPS13, RPS14, RPS15, RPS28, ARMC6, BOLA2, BOLA2B, CDC123, CKS1B, CMSS1, DDX39A, DNAJC9, FAM60A, HN1, MRPL47, NDUFA13, PET100, PFDN4, PSMA7, RNASEH2A, ROMO1, RPL35A, SLIRP, SLMO2, SNRPF, SNRPG, TPRKB, TXNDC17, UBL5, USMG5, AHNAK, APOD, ATP1A1, B2M, CD44, CD63, CTSB, CTSD, FOS, GRN, HLA-A, HLA-B, HLA-C, HLA-E, HLA-H, LAMP2, LGALS3, LGALS3BP, NPC2, PSAP, SERPINE2, TAPBP, TIMP2, CTSO, KLF4, LEF1-AS1, STOM, TAPBPL, VAT1, ACTA2, C6orf226, CCR10, CITED1, CORO1A, CXCR4, DDX17, F1139051, FMN1, FRZB, FSTL3, FTH1, HLA-DRB5, IDI2-AS1, JMJD7, LCP1, LINC00518, LOC100506714, LOC100507463, LY96, NMRK1, P2RX4, PIK3IP1, PYGB, RAB27A, RBP7, RNF213, RTP4, SDCBP, SLC22A18, SLC7A5P1, SP100, SPESP1, SPINT1, ST3GAL6-AS1, ST6GALNAC2, TFAP2A, TRIM22, TTLL1 and UCN2;
• or
• b) one or more genes or polypeptides selected from the group consisting of BZW2, CCT3, CDK4, GPATCH4, ISYNA1, MDH2, PPIA, RPL31, RPL37A, RPL41, RPS21, RPS27A, RUVBL2, SAE1, UBA52, AHCY, C17orf76-AS1, C19orf48, C1QBP, CCT6A, CHCHD2, CTPS1, EEF1G, EIF2S3, EIF3K, EIF4A1, FARSA, FBL, FKBP4, GAS5, GNB2L1, GPI, HNRNPA1, HNRNPC, IDH2, ILF2, NACA, NCL, NME1, NOLC1, NONO, PABPC1, PAICS, PFN1, POLD2, PPA1, PTMA, PUF60, RPL10A, RPL11, RPL12, RPL13, RPL13A, RPL13AP5, RPL17, RPL18, RPL18A, RPL21, RPL26, RPL27, RPL28, RPL29, RPL3, RPL36, RPL36A, RPL37, RPL4, RPL5, RPL6, RPL8, RPLP0, RPLP1, RPS10, RPS11, RPS13, RPS14, RPS15, RPS15A, RPS16, RPS17, RPS17L, RPS18, RPS19, RPS23, RPS24, RPS27, RPS28, RPS3, RPS4X, RPS5, RPS6, RPS7, RPS8, RPS9, RPSA, RRS1, SERPINF1, SET, SHMT2, SLC19A1, SLC25A13, SNHG6, SNRPE, SOX4, SSR2, TIMM50, TOP1MT, TUBB, UQCRFS1, UQCRH, VDAC2, ACTB, AEN, ANP32E, APP, ARMC6, ATP5A1, ATP5D, ATP5G2, ATP5G3, BOLA2, BOLA2B, BOP1, BTF3, C20orf112, C6orf48, CA14, CACYBP, CBX5, CCT2, CCT4, CCT7, CDC123, CDCA7, CFL1, CKS1B, CMSS1, CNRIP1, CS, DARS, DCAF13, DCT, DCTPP1, DDX21, DDX39A, DDX39B, DLL3, DNAJC9, EEF1B2, EEF1D, EEF2, EIF3E, EIF3F, EIF3G, EIF3M, EIF4EBP2, ENO1, EXOSC5, FAM174B, FAM60A, FAM92A1, FBLN1, FOXRED2, FTL, FUS, GABARAP, GGH, GNL3, GRWD1, H3F3A, H3F3AP4, HMGA1, HMGB1, HN1, HNRNPA1P10, HNRNPH1, HNRNPM, HSP90AB1, HSPA8, HSPD1, IFRD2, ILF3, IMPDH2, ITM2C, KIAA0101, LDHB, LSM4, LSM7, LYPLA1, MAGEA4, MAGEC1, MCM7, METAP2, MID1, MIR4461, MKI67IP, MLLT11, MPZL1, MRPL15, MRPL37, MRPL4, MRPL47, MRPS12, MRPS21, NDUFA11, NDUFA13, NDUFS2, NME2, NOP16, NPM1, NREP, PA2G4, PAFAH1B3, PET100, PFDN2, PFDN4, PGAM1, PIH1D1, PLEKHJ1, POLR1D, POLR2E, PPP2R1A, PRMT1, PSMA7, PSMD4, RAN, RBM34, RNASEH2A, RNF2, ROMO1, RPAIN, RPL10, RPL14, RPL15, RPL19, RPL22, RPL27A, RPL30, RPL32, RPL35, RPL35A, RPL39, RPL7, RPL7A, RPL9, RPLP2, RPS12, RPS2, RPS20, RPS25, RPS3A, RQCD1, RSL1D1, RTKN, SCD, SCNM1, SERBP1, SF3B4, SKP2, SLC25A3, SLC25A6, SLIRP, SLMO2, SMARCA4, SMIM15, SMS, SNAI2, SNHG15, SNRPB, SNRPC, SNRPD1, SNRPD2, SNRPF, SNRPG, SRM, SRP14, SSB, TIMM13, TIMM44, TMC6, TP53, TPI1, TPRKB, TRAP1, TRIM28, TRPM1, TSR1, TUBA1B, TULP4, TXNDC17, TYMS, UBL5, UCK2, UHRF1, USMG5, USP22, VCY1B, VPS72, XIST, YWHAE, ZFAS1, ZNF286A, AHNAK, APOD, ATP1A1, B2M, CD44, CD63, CTSB, CTSD, FOS, GRN, HLA-A, HLA-B, HLA-C, HLA-E, HLA-H, LAMP2, LGALS3, LGALS3BP, NPC2, PSAP, SERPINE2, TAPBP, TIMP2, A2M, ACSL3, AEBP1, AGA, APOC2, APOE, ATP1B1, CD151, CD47, CD58, CD59, CDH19, CSPG4, CST3, CTSA, CTSL1, CTSO, CYP27A1, DAG1, DDR1, EEA1, EMP1, EVA1A, FBXO32, FGFR1, GAA, GPNMB, GSN, HLA-F, HSPA1A, IRF4, ITGA3, KCNN4, KLF4, LEF1-AS1, LRPAP1, MFGE8, MIA, MT2A, NEAT1, NPC1, NSG1, PROS1, S100A6, S100B, SAT1, SCARB2, SDC3, SEC11C, SERPINA3, SGK1, SLC26A2, SLC5A3, STOM, STX7, TAPBPL, TIMP1, TIMP3, TM4SF1, TMED10, TPP1, TSC22D3, TYR, UBC, VAT1, WBP2, XAGE1D, ACSL4, ACTA2, ADM, ANGPTL4, ANXA1, ANXA2, APLP2, APOL1, ARL6IP5, ARSA, ATF3, ATP1B3, ATP6V0C, BACE2, BBX, BCL6, C4A, C6orf226, CALU, CARD16, CASP1, CAST, CAV1, CAV2, CCND3, CCR10, CD9, CDH1, CHI3L1, CITED1, CLIC4, CORO1A, CRELD1, CRYAB, CSGALNACT1, CXCR4, CYP4V2, DCBLD2, DDX17, DDX5, DPYSL2, DUSP4, DUSP6, ECM1, EGR1, EPHX2, ERBB3, EZH1, FAM3C, FCGR2C, FCRLA, F1139051, FLJ43663, FLNA, FMN1, FRZB, FSTL3, FTH1, GADD45B, GATSL3, GEM, GJB1, GOLGB1, GPR155, GPR56, HLA-DRB5, HLA-G, HPCAL1, HTATIP2, IDI2-AS1, IFI27, IFI27L2, IFI35, IFI6, IGF1R, IGFBP7, IGSF8, IL1RAP, IL6ST, ITGA6, ITGA7, ITGB1, ITGB3, ITM2B, JMJD7, JUN, KLF6, LAMB2, LCP1, LEPROT, LGALS1, LGMN, LINC00518, LOC100126784, LOC100506190, LOC100506714, LOC100507463, LPL, LY6E, LY96, LYRM9, MAGEC2, MALAT1, MATN2, MCAM, MFI2, MMP14, MPZ, MT1E, MT1M, MT1X, MTRNR2L1, MTRNR2L10, MTRNR2L2, MTRNR2L3, MTRNR2L4, MTRNR2L5, MTRNR2L6, MTRNR2L7, MTRNR2L8, MYO1D, NAV2, NFE2L1, NFKBIA, NFKBIZ, NMRK1, NNMT, NR4A1, P2RX4, PAGE5, PDE4DIP, PDK4, PERP, PIK3IP1, PLP2, PRKCDBP, PRNP, PRSS23, PSMB9, PTRF, PYGB, QPCT, RAB27A, RBP7, RDH5, RNF145, RNF213, RPS4Y1, RTP4, S100A1, S100A13, SCCPDH, SDCBP, SEL1L, SEMA3B, SERINC1, SERPINA1, SGCE, SHC4, SLC20A1, SLC22A18, SLC39A14, SLC7A5P1, SLC7A8, SNX9, SOD1, SORT1, SP100, SPESP1, SPINT1, SPON2, SPP1, SPRY2, SQSTM1, SRPX, ST3GAL6-AS1, ST6GALNAC2, STRIP2, SYNE2, SYNGR2, SYPL1, TF, TFAP2A, TGOLN2, THBD, TMBIM6, TMED9, TMEM255A, TMEM66, TMX4, TNC, TNFSF4, TRIM22, TRIML2, TSPYL2, TTLL1, TXNIP, UCN2, UPP1, WDFY1, ZBTB20 and ZBTB38;
• or
• c) one or more genes or polypeptides selected from Table 27B.1, or
• a malignant cell gene signature comprising one or more genes or polypeptides selected from the group consisting of:
• BZW2, CCT3, CDK4, GPATCH4, ISYNA1, MDH2, PPIA, RPL31, RPL37A, RPL41, RPS21, RPS27A, RUVBL2, SAE1, UBA52, C17orf76-AS1, C1QBP, CTPS1, EEF1G, EIF2S3, EIF3K, EIF4A1, FBL, GAS5, GNB2L1, GPI, HNRNPA1, HNRNPC, IDH2, ILF2, NACA, NCL, NOLC1, NONO, PABPC1, PFN1, PPA1, PTMA, RPL10A, RPL11, RPL12, RPL13, RPL13A, RPL13AP5, RPL17, RPL18, RPL18A, RPL21, RPL26, RPL28, RPL29, RPL3, RPL36A, RPL37, RPL4, RPL5, RPL6, RPL8, RPLP0, RPLP1, RPS10, RPS11, RPS15A, RPS16, RPS17, RPS17L, RPS18, RPS19, RPS23, RPS24, RPS27, RPS3, RPS4X, RPS5, RPS6, RPS7, RPS8, RPS9, RPSA, SERPINF1, SET, SHMT2, SNHG6, SNRPE, SOX4, SSR2, TIMM50, TUBB, UQCRFS1, UQCRH, VDAC2, ACTB, AEN, ANP32E, ATP5A1, ATP5G2, C20orf112, CA14, CBX5, CCT2, CFL1, CNRIP1, CS, DCAF13, DCT, DDX39B, DLL3, EIF4EBP2, FAM174B, FBLN1, FOXRED2, FTL, FUS, GABARAP, GRWD1, H3F3A, H3F3AP4, HMGA1, HNRNPA1P10, HSPA8, ITM2C, KIAA0101, MAGEA4, METAP2, MID1, MIR4461, MLLT11, MPZL1, MRPS21, NDUFS2, PA2G4, PAFAH1B3, PFDN2, PGAM1, PIH1D1, PPP2R1A, PSMD4, RAN, RBM34, RNF2, RPAIN, RPS12, SCD, SCNM1, SF3B4, SKP2, SLC25A3, SMS, SNAI2, SRP14, TMC6, TP53, TRPM1, TSR1, TUBA1B, TULP4, USP22, VCY1B, VPS72, YWHAE, ZNF286A, AHNAK, APOD, ATP1A1, B2M, CD44, CD63, CTSB, CTSD, FOS, GRN, HLA-A, HLA-B, HLA-C, HLA-E, HLA-H, LAMP2, LGALS3, LGALS3BP, NPC2, PSAP, SERPINE2, TAPBP, TIMP2, A2M, ACSL3, AEBP1, AGA, APOE, ATP1B1, CD151, CD47, CD58, CD59, CDH19, CSPG4, CST3, CTSA, CTSL1, DAG1, DDR1, EEA1, EMP1, EVA1A, FBXO32, FGFR1, GAA, GPNMB, GSN, HLA-F, HSPA1A, ITGA3, KCNN4, KLF4, LRPAP1, MFGE8, MIA, MT2A, NEAT1, NPC1, NSG1, PROS1, S100A6, S100B, SAT1, SCARB2, SDC3, SERPINA3, SGK1, SLC26A2, SLC5A3, STOM, TAPBPL, TIMP1, TIMP3, TM4SF1, TMED10, TPP1, TSC22D3, TYR, UBC, ACSL4, ADM, ANGPTL4, ANXA1, ANXA2, APLP2, ARL6IP5, ATF3, ATP1B3, BACE2, BBX, BCL6, CALU, CASP1, CAST, CAV1, CCND3, CD9, CHI3L1, CLIC4, CRELD1, CRYAB, CSGALNACT1, DCBLD2, DDX5, DPYSL2, DUSP4, DUSP6, ECM1, EGR1, EPHX2, ERBB3, EZH1, FAM3C, FCGR2C, FCRLA, FLJ43663, GADD45B, GEM, GOLGB1, HPCAL1, HTATIP2, IFI35, IGF1R, IL1RAP, IL6ST, ITGA6, ITGB1, ITGB3, ITM2B, JUN, KLF6, LEPROT, LGALS1, LPL, MAGEC2, MFI2, MT1E, MT1M, MT1X, NFKBIA, NFKBIZ, NNMT, NR4A1, PDK4, PLP2, PRKCDBP, PRNP, PRSS23, PSMB9, PTRF, RNF145, RPS4Y1, SCCPDH, SEL1L, SEMA3B, SGCE, SLC20A1, SLC39A14, SOD1, SPRY2, SQSTM1, SRPX, SYNGR2, SYPL1, TF, TGOLN2, TMED9, TMEM66, TMX4, TNC, UPP1, ZBTB20 and ZBTB38, or
• an immune cell exclusion gene signature comprising:
• a) one or more genes or polypeptides selected from the group consisting of BZW2, CCT3, CDK4, GPATCH4, ISYNA1, MDH2, RUVBL2, AHCY, CCT6A, FKBP4, NME1, PAICS, POLD2, PUF60, RRS1, SLC19A1, SLC25A13, TOP1MT, HSP90AB1, RTKN, APOC2, CYP27A1, IRF4, SEC11C, STX7, WBP2, XAGE1D, PAGE5 and WDFY1;
• or
• b) one or more genes or polypeptides selected from the group consisting of BZW2, CCT3, CDK4, GPATCH4, ISYNA1, MDH2, PPIA, RPL31, RPL37A, RPL41, RPS21, RPS27A, RUVBL2, SAE1, UBA52, AHCY, C17orf76-AS1, C19orf48, C1QBP, CCT6A, CHCHD2, CTPS1, EEF1G, EIF2S3, EIF3K, EIF4A1, FARSA, FBL, FKBP4, GAS5, GNB2L1, GPI, HNRNPA1, HNRNPC, IDH2, ILF2, NACA, NCL, NME1, NOLC1, PABPC1, PAICS, PFN1, POLD2, PPA1, PTMA, PUF60, RPL10A, RPL11, RPL12, RPL13, RPL13A, RPL13AP5, RPL17, RPL18, RPL18A, RPL21, RPL26, RPL27, RPL28, RPL29, RPL3, RPL36, RPL36A, RPL37, RPL4, RPL5, RPL6, RPL8, RPLP0, RPLP1, RPS10, RPS11, RPS13, RPS14, RPS15, RPS15A, RPS16, RPS17, RPS17L, RPS18, RPS19, RPS23, RPS24, RPS27, RPS28, RPS3, RPS4X, RPS5, RPS6, RPS7, RPS8, RPS9, RPSA, RRS1, SERPINF1, SET, SHMT2, SLC19A1, SLC25A13, SNHG6, SNRPE, SOX4, SSR2, TIMM50, TOP1MT, TUBB, UQCRFS1, UQCRH, VDAC2, APP, ATP5D, ATP5G3, BOP1, BTF3, C6orf48, CACYBP, CCT4, CCT7, CDCA7, DARS, DCTPP1, DDX21, EEF1B2, EEF1D, EEF2, EIF3E, EIF3F, EIF3G, EIF3M, ENO1, EXOSC5, FAM92A1, GGH, GNL3, HMGB1, HNRNPH1, HNRNPM, HSPD1, IFRD2, ILF3, IMPDH2, LDHB, LSM4, LSM7, LYPLA1, MAGEC1, MCM7, MKI67IP, MRPL15, MRPL37, MRPL4, MRPS12, NDUFA11, NME2, NOP16, NPM1, NREP, PLEKHJ1, POLR1D, POLR2E, PRMT1, RPL10, RPL14, RPL15, RPL19, RPL22, RPL27A, RPL30, RPL32, RPL35, RPL39, RPL7, RPL7A, RPL9, RPLP2, RPS2, RPS20, RPS25, RPS3A, RQCD1, RSL1D1, SERBP1, SLC25A6, SMARCA4, SMIM15, SNHG15, SNRPB, SNRPC, SNRPD1, SNRPD2, SRM, SSB, TIMM13, TIMM44, TPI1, TRAP1, TRIM28, TYMS, UCK2, UHRF1, XIST, ZFAS1, AHNAK, APOD, ATP1A1, B2M, CD44, CD63, CTSB, CTSD, FOS, GRN, HLA-A, HLA-B, HLA-C, HLA-E, HLA-H, LAMP2, LGALS3, LGALS3BP, NPC2, PSAP, SERPINE2, TAPBP, TIMP2, A2M, ACSL3, AEBP1, AGA, APOC2, APOE, ATP1B1, CD151, CD47, CD58, CD59, CDH19, CSPG4, CST3, CTSA, CTSL1, CTSO, CYP27A1, DAG1, DDR1, EEA1, EMP1, EVA1A, FBXO32, FGFR1, GAA, GPNMB, GSN, HLA-F, HSPA1A, IRF4, ITGA3, KCNN4, LEF1-AS1, LRPAP1, MFGE8, MIA, MT2A, NEAT1, NPC1, NSG1, PROS1, S100A6, S100B, SAT1, SCARB2, SDC3, SEC11C, SERPINA3, SGK1, SLC26A2, SLC5A3, STX7, TIMP1, TIMP3, TM4SF1, TMED10, TPP1, TSC22D3, TYR, UBC, VAT1, WBP2, XAGE1D, APOL1, ARSA, ATP6V0C, C4A, CARD16, CAV2, CDH1, CYP4V2, FLNA, GATSL3, GJB1, GPR155, GPR56, HLA-G, IFI27, IFI27L2, IFI6, IGFBP7, IGSF8, ITGA7, LAMB2, LGMN, LOC100126784, LOC100506190, LY6E, LYRM9, MALAT1, MATN2, MCAM, MMP14, MPZ, MTRNR2L1, MTRNR2L10, MTRNR2L2, MTRNR2L3, MTRNR2L4, MTRNR2L5, MTRNR2L6, MTRNR2L7, MTRNR2L8, MYO1D, NAV2, NFE2L1, PDE4DIP, PERP, QPCT, RDH5, S100A1, S100A13, SERINC1, SERPINA1, SHC4, SLC7A8, SNX9, SORT1, SPON2, SPP1, STRIP2, SYNE2, THBD, TMBIM6, TMEM255A, TNFSF4, TRIML2, TSPYL2 and TXNIP.