Interferon pathway genes regulate and predict efficacy of immunotherapy
The present invention includes methods for treating cancer and selecting a patient for immunotherapy administration.
1 . A method for treating cancer in a subject in need thereof, the method comprising:
measuring expression level of an interferon stimulating genes resistance signature (ISG.RS) metagene in a tumor from the subject and/or in a cancer cell from the subject;
measuring expression level of an interferon gene signature (IFNG.GS) metagene in a tumor from the subject and/or in an intratumoral immune cell from the subject; and
administering an immunotherapy comprising an immune checkpoint blockade (ICB) to the subject when the measured expression level of the IFNG.GS metagene is greater than the measured expression level of the ISG.RS metagene, or
administering an alternative cancer treatment to the subject when the measured expression level of the ISG.RS metagene is greater than the measured expression level of the IFNG.GS metagene, wherein the subject is not administered the immunotherapy,
thereby treating the cancer in the subject; wherein:
the cancer is melanoma;
the ISG.RS metagene comprises IFI27, IRF7, USP18, BST2, CXCL10, DDX60, HERC6, HLA-B, HLA-G, IFI35, IFI44, IFI44L, IFIT1, IFIT3, ISG15, LGALS3BP, LY6E, MX1, MX2, OAS3, OASL, PLSCR1, STAT1, TRIM14, HSD17B1, OAS1, CA2, CCNA1, CXCL1, GALC, IFI6, IFITM1, LAMP3, MCL1, ROBO1, SLC6A15, THBS1, and TIMP3; and
the IFNG.GS metagene comprises TNFSF10, IRF9, EPSTI1, PARP12, TRIM25, CASP7, UPP1, B2M, IRF4, SRI, NFKBIA, OAS2, RSAD2, XAF1, SP110, IFITM3, GBP4, IRF8, IFIH1, UBE2L6, ADAR, STAT2, CXCL9, IL10RA, PLA2G4A, TRIM21, PTGS2, DDX58, IL15, NLRC5, NMI, IDO1, PSMB10, CXCL11, SAMD9L, RTP4, PTPN2, TNFAIP2, IFITM2, SOCS1, CASP1, ICAM1, WARS, PSME1, ISG20, FCGR1A, SOCS3, HLA-DMA, TNFAIP6, TRIM26, VCAM1, CD274, CIITA, NAMPT, GPR18, FPR1, PRIC285, PSME2, SERPING1, CCL5, RNF31, SOD2, PSMA3, RNF213, PELI1, CFB, CD86, HLA-DQA1, GCH1, PNP, CCL7, PTPN6, SPPL2A, IL4R, DHX58, CASP8, IFI30, CCL2, FGL2, SECTM1, IL15RA, CD40, HLA-DRB1, GBP6, LCP2, MT2A, RIPK1, PSMB2, TDRD7, HIF1A, PFKP, ZBP1, PDE4B, IL7, BPGM, FTSJD2, AUTS2, RIPK2, MYD88, PSMA2, NOD1, TAPBP, SLC25A28, PTPN1, SSPN, NUP93, MTHFD2, CDKN1A, NFKB1, BATF2, LATS2, IRF5, SLAMF7, ISOC1, P2RY14, STAT3, NCOA3, GZMA, IFNAR2, CD74, RAPGEF6, CASP4, OGFR, ARL4A, LYSMD2, CSF2RB, C1R, METTL7B, ST8SIA4, CD38, PSMB9, BANK1, TOR1B, ITGB7, RBCK1, FAS, LAP3, SAMHD1, CMPK2, MVP, TXNIP, ST3GAL5, PARP14, CASP3, IFIT2, CD69, CMKLR1, TAP1, EIF2AK2, PIM1, XCL1, IL2RB, IRF1, BTG1, CFH, VAMP5, IL18BP, IRF2, ZNFX1, PSMB8, ARID5B, MARCH1, TNFAIP3, APOL6, STAT4, JAK2, PML, TRAFD1, SELP, KLRK1, CIS, EIF4E3, HLA-A, PNPT1, VAMP8, and IL6.
2 . The method of claim 1 , wherein the ICB is selected from the group consisting of anti-CTLA4, anti-PD1, anti-PDL1, and any combination thereof,
and/or the immunotherapy further comprises adoptive cell therapy comprising CAR T cell therapy or TCR engineered T cell therapy.
3 . The method of claim 2 , wherein the ICB comprises anti-PD1 and anti-CTLA4.
4 . The method of claim 1 , wherein:
(a) the alternative treatment comprises one or more selected from the group consisting of chemotherapy, radiation, surgery, an alternative immune checkpoint blockade (ICB), an alternative adoptive cell therapy, an alternative immunotherapy, and any combination thereof, and/or
(b) the alternative treatment comprises a treatment that increases the IFNG.GS metagene expression level and/or decreases the ISG.RS metagene expression level.
5 . The method of claim 4 , wherein:
(a) the treatment that decreases the ISG.RS metagene expression level comprises one or more selected from the group consisting of an IFN blocking agent, an IFN receptor blocking agent, a JAK inhibitor, a STAT inhibitor, an alternative adoptive cell therapy, a small molecule, and any combination thereof; and/or
(b) the treatment that increases the IFNG.GS metagene expression level comprises one or more selected from the group consisting of anti-CTLA4, anti-PDL1, anti-TIM3, anti-LAG3, anti-2B4, anti-4-1BB, anti-GITR, anti-VISTA, anti-CD40, cGAS/STING agonists, RIG-I agonists, TLR agonists, MDA5 agonists, radiation, chemotherapy, molecularly targeted agents, epigenetic therapies, and any combination thereof.
6 . The method of claim 1 , wherein the intratumoral immune cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a macrophage, a dendritic cell, a myeloid cell, an innate lymphoid cell (ILC), and a CD8+ cell.
7 . The method of claim 1 , wherein measuring the expression level comprises at least one method selected from the group consisting of RNA-Seq, q-PCR, RT-PCR, sequencing, transcriptomics, and microarray.
8 . A method for treating cancer in a subject in need thereof, the method comprising:
measuring expression level of an interferon stimulating genes resistance signature (ISG.RS) metagene in a tumor from the subject and/or in a cancer cell from the subject;
measuring expression level of an interferon gene signature (IFNG.GS) metagene in a tumor from the subject and/or in an intratumoral immune cell from the subject;
calculating a ratio of the expression level of the IFNG.GS metagene over the expression level of the ISG.RS metagene; and
administering an immunotherapy comprising an immune checkpoint blockade (ICB) to the subject when the ratio is increased in comparison to that of a reference sample; or
administering an alternative cancer treatment to the subject when the ratio is not increased in comparison to that of a reference sample, wherein the subject is not administered the immunotherapy,
thereby treating the cancer in the subject; wherein:
the cancer is melanoma;
the ISG.RS metagene comprises IFI27, IRF7, USP18, BST2, CXCL10, DDX60, HERC6, HLA-B, HLA-G, IFI35, IFI44, IFI44L, IFIT1, IFIT3, ISG15, LGALS3BP, LY6E, MX1, MX2, OAS3, OASL, PLSCR1, STAT1, TRIM14, HSD17B1, OAS1, CA2, CCNA1, CXCL1, GALC, IFI6, IFITM1, LAMP3, MCL1, ROBO1, SLC6A15, THBS1, and TIMP3; and
the IFNG.GS metagene comprises TNFSF10, IRF9, EPSTI1, PARP12, TRIM25, CASP7, UPP1, B2M, IRF4, SRI, NFKBIA, OAS2, RSAD2, XAF1, SP110, IFITM3, GBP4, IRF8, IFIH1, UBE2L6, ADAR, STAT2, CXCL9, IL10RA, PLA2G4A, TRIM21, PTGS2, DDX58, IL15, NLRC5, NMI, IDO1, PSMB10, CXCL11, SAMD9L, RTP4, PTPN2, TNFAIP2, IFITM2, SOCS1, CASP1, ICAM1, WARS, PSME1, ISG20, FCGR1A, SOCS3, HLA-DMA, TNFAIP6, TRIM26, VCAM1, CD274, CIITA, NAMPT, GPR18, FPR1, PRIC285, PSME2, SERPING1, CCL5, RNF31, SOD2, PSMA3, RNF213, PELI1, CFB, CD86, HLA-DQA1, GCH1, PNP, CCL7, PTPN6, SPPL2A, IL4R, DHX58, CASP8, IFI30, CCL2, FGL2, SECTM1, IL15RA, CD40, HLA-DRB1, GBP6, LCP2, MT2A, RIPK1, PSMB2, TDRD7, HIF1A, PFKP, ZBP1, PDE4B, IL7, BPGM, FTSJD2, AUTS2, RIPK2, MYD88, PSMA2, NOD1, TAPBP, SLC25A28, PTPN1, SSPN, NUP93, MTHFD2, CDKN1A, NFKB1, BATF2, LATS2, IRF5, SLAMF7, ISOC1, P2RY14, STAT3, NCOA3, GZMA, IFNAR2, CD74, RAPGEF6, CASP4, OGFR, ARL4A, LYSMD2, CSF2RB, C1R, METTL7B, ST8SIA4, CD38, PSMB9, BANK1, TOR1B, ITGB7, RBCK1, FAS, LAP3, SAMHD1, CMPK2, MVP, TXNIP, ST3GAL5, PARP14, CASP3, IFIT2, CD69, CMKLR1, TAP1, EIF2AK2, PIM1, XCL1, IL2RB, IRF1, BTG1, CFH, VAMP5, IL18BP, IRF2, ZNFX1, PSMB8, ARID5B, MARCH1, TNFAIP3, APOL6, STAT4, JAK2, PML, TRAFD1, SELP, KLRK1, CIS, EIF4E3, HLA-A, PNPT1, VAMP8, and IL6.
9 . The method of claim 8 , wherein the ICB is selected from the group consisting of anti-CTLA4, anti-PD1, anti-PDL1, and any combination thereof, and/or the immunotherapy further comprises adoptive cell therapy comprising CAR T cell therapy or TCR engineered T cell therapy.
10 . The method of claim 8 , wherein the ICB comprises anti-PD1 and anti-CTLA4.
11 . The method of claim 8 , wherein:
(a) the alternative treatment comprises one or more selected from the group consisting of chemotherapy, radiation, surgery, an alternative immune checkpoint blockade (ICB), an alternative adoptive cell therapy, an alternative immunotherapy, and any combination thereof; and/or
(b) the alternative treatment comprises a treatment that increases the IFNG.GS metagene expression level and/or decreases the ISG.RS metagene expression level.
12 . The method of claim 11 , wherein:
(a) the treatment that decreases the ISG.RS metagene expression level comprises one or more selected from the group consisting of an IFN blocking agent, an IFN receptor blocking agent, a JAK inhibitor, a STAT inhibitor, an alternative adoptive cell therapy, a small molecule, and any combination thereof; and/or
(b) the treatment that increases the IFNG.GS metagene expression level comprises one or more selected from the group consisting of anti-CTLA4, anti-PDL1, anti-TIM3, anti-LAG3, anti-2B4, anti-4-1BB, anti-GITR, anti-VISTA, anti-CD40, cGAS/STING agonists, RIG-I agonists, TLR agonists, MDA5 agonists, radiation, chemotherapy, molecularly targeted agents, epigenetic therapies, and any combination thereof.
13 . The method of claim 8 , wherein the intratumoral immune cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a macrophage, a dendritic cell, a myeloid cell, an innate lymphoid cell (LC), and a CD8+ cell.
14 . The method of claim 8 , wherein measuring the expression level comprises at least one method selected from the group consisting of RNA-Seq, q-PCR, RT-PCR, sequencing, transcriptomics, and microarray.