| CPC G16H 50/50 (2018.01) [G16B 25/10 (2019.02); G16H 20/10 (2018.01)] | 19 Claims |
|
1. A method for determining a tumor microenvironment (TME) type of a subject, the method comprising:
using at least one computer hardware processor to perform:
obtaining RNA expression data for the subject, the RNA expression data indicating RNA expression levels for at least three genes in each of at least two gene groups of a set of gene groups, the set of gene groups including:
(a) Conventional dendritic cells type 1 (cDC1) group: XCR1, CLEC9A, Clorf54, BATF3, WDFY4, and HLA-DOB;
(b) Conventional dendritic cells type 2 (cDC2) group: ITGAX, HLA-DRA, HLA-DRB1, CD1C, FCER1A, CLEC10A, and AMICA1;
(c) Plasmacytoid dendritic cells (pDC) group: IL3RA, CLEC4C, CCR2, CXCR3, GZMB, DERL3, LILRA4, and SCT;
(d) M1 cytokines group: CXCL10, IL23A, IL1B, IL12B, TNF, and CXCL9;
(e) Panmacrophage signature group: C1QC, CSF1R, CD163, SIGLEC1, C1QA, VSIG4, MSR1, and CD68;
(f) Tertiary Lymphoid Structure (TLS) group: CXCL10, SELL, LAMP3, FDCSP, CD86, CXCL13, PTPRCAP, CCR7, LTA, CXCR3, CCL21, CCL19, JCHAIN, CXCL9, and TNFRSF17;
(g) Proinflammatory cytokines group: IL23A, IFNB1, IL1A, IL1B, TNF, CXCL2, IL6, IL26, CCL2, CCL4, LIF, and CCL3;
(h) Anti-tumor chemokines group: CXCL10, CXCL9, CXCL13, XCL1, CCL5, CCL21, CCL19, and XCL2;
(i) Pro-tumor chemokines group: CCL26, CXCL6, CCL20, CXCL8, CXCL1, CCL18, CCL17, and CCL22;
(j) Myeloid checkpoints group: PDCD1LG2, HAVCR2, CD274, and C10orf54;
(k) Lymphoid checkpoints group: BTLA, TIGIT, LAG3, PVRIG, PDCD1, and CTLA4;
(l) Cytotoxic cell inactivation group: PIM2, SERPINB9, LGALS9, CD5, KLRB1, FASLG, KLRD1, LAIR1, LAIR2, and SIGLEC7;
(m) Regulatory B (Breg) cells group: ZBTB32, NFKBID, SOX5, EBI3, and ZBTB20;
(n) Myeloid suppression group: IL10, FGL2, EBI3, CYBB, IL4I1, TGFBI, IDO1, PTGS2, and MSR1;
(o) Phagocytosis inhibition group: LILRB3, LILRB1, FCGR2B, LILRB4, SIRPA, SIGLEC10, LILRB2, PECAM1, CD300A, CD300LF, and CD33;
(p) Stromal suppression group: IL11, TGFB2, TDO2, TSLP, IL6, TGFB3, and TGFBI;
(q) Exclusion of cytotoxic T lymphocytes (CTL) group: GAS6, VEGFA, PDGFC, FGF2, EDNRB, TNFAIP6, and CXCL12;
(r) Endothelium group: ECSCR, NOS3, MMRN1, VWF, CLEC14A, FLT1, KDR, ROBO4, ENG, CDH5, and MMRN2;
(s) Carcinogenic-associated fibroblast (CAF) group: FBLN1, COL1A1, PDGFRB, CXCL12, COL6A1, COL5A1, FGF2, FAP, PDGFRA, MMP2, MMP3, COL1A2, CD248, FN1, LUM, MFAP5, LRP1, COL11A1, COL6A3, COL6A2, LGALS1, and ACTA2;
(t) Epithelial-mesenchymal transition (EMT) signature group: RUNX2, FOXM1, SNAI1, TWIST1, and SNAI2;
(u) Adipocytes group: GPD1, LBP, PTGER3, DLAT, FABP4, LEP, PLIN1, ADIPOQ, PPP1R1A, ADH1B, LIPE, and COL4A4;
(v) Metastasis signature group: MMP9, HPSE, PARP1, CDH2, RCC2, and SERPINH1;
(w) Metabolic suppression of CTL group: SPHK1, MSR1, ADORA2A, and ENTPD1;
(x) Hypoxia factors group: LOX, FUT11, PGK1, CA12, TPI1, PDK1, EPAS1, LDHA, SLC2A1, PFKFB3, P4HA1, ALDOA, CA9, HK2, and NDRG1;
(y) Autophagy group: ATG12, ATG9A, TFEB, RB1CC1, MAP1LC3B, GABARAPL2, ATG4B, ATG7, GABARAP, VMP1, ATG14, GABARAPL1, ATG13, and NBR1;
(z) Acidosis group: SLC16A1, SLC16A4, MAPK14, and SLC9A1;
(aa) Senescence group: CDKN2A, CDKN1A, CDKN2B, GLB1, SERPINE1, DPP4, CEBPB, BCL2L1, BCL2L2, TNFRSF10D, ITGB3, IGFBP3, MMP3, CCL2, IL6, CXCL8, CXCL1, IL1B, TGFB1, GDF15, IGFBP7, PLAU, STAT1, IGFBP2, and ATF3;
(ab) Apoptosis group: BCL10, BIK, CASP6, TNFRSF12A, CASP2, CASP3, CASP7, CASP8, CYLD, FAS, IER3, PMAIP1, BCL2L11, TNFRSF10A, TNFRSF10B, APAF1, XAF1, and CASP8AP2; and
(ac) Glycolysis group: ALDOA, TPI1, GPD2, PGK1, LDHA, PFKP, BPGM, ENO1, GPI, and SLC16A3;
generating a TME signature for the subject by determining, using the RNA expression data, a gene group score for each gene group in the at least two gene groups;
determining a distance between the TME signature and predetermined TME clusters, the predetermined TME clusters each being associated with one of a plurality of TME types;
identifying, using the determined distance and from among the plurality of TME types, a TME type for the subject; and
identifying and administering to the subject at least one therapeutic agent using the TME type of the subject, wherein identifying and administering to the subject the at least one therapeutic agent based on the TME type of the subject comprises:
identifying and administering to the subject an immune checkpoint inhibitor comprising an anti-TGF-β antibody, an anti-PDGFR antibody, or an anti-VEGF antibody as the at least one therapeutic agent when the subject is identified as having an Immune-Enriched, Fibrotic (IE/F), Fibrotic, Angiogenic, Myeloid (F/A/M), or Fibrotic, Hypoxic (F/H) type TME type,
identifying and administering to the subject a TKI as the at least one therapeutic agent when the subject is identified as having an IE/F, F/A/M, or F/H type TME type,
identifying and administering to the subject an immune checkpoint inhibitor comprising an anti-IL-6 antibody as the at least one therapeutic agent when the subject is identified as having an IE/F or Highly Immune-Enriched, Inflamed (IE/Inf) type TME type,
identifying and administering to the subject an immune checkpoint inhibitor comprising an anti-CD276 antibody as the at least one therapeutic agent when the subject is identified as having an F/A/M or F/H type TME type,
identifying and administering to the subject an immune checkpoint inhibitor comprising an anti-PD-L2 antibody or anti-SIRPa antibody as the at least one therapeutic agent when the subject is identified as having an F/A/M or IE/F type TME type,
identifying and administering to the subject an immune checkpoint inhibitor comprising an anti-PD-1 antibody as the at least one therapeutic agent when the subject is identified as having a B-Cell Enriched, Angiogenic (IE/B/A) or a Lymphoid-Cell Enriched (IE/L) type TME type, and/or
identifying and administering to the subject an immune checkpoint inhibitor comprising an anti-PDL-1 antibody as the at least one therapeutic agent when the subject is identified as having an Immune-Enriched, Hypoxic (IE/H) or IE/Inf type TME type.
|