IP Library › Granted Patent US 12,462,941
Granted Patent B2
US 12,462,941 · App. 18/634,443 · Granted Nov 4, 2025

Pan-cancer tumor microenvironment classification based on immune escape mechanisms and immune infiltration

Inventors: Sofya Kust (Yerevan, AM); Anastasia Zotova (Moscow, RU); Elena Ocheredko (Yerevan, AM); Alexander Bagaev (Waltham, MA); Maria Savchenko (Yerevan, AM); Nadezhda Lukashevich (Yerevan, AM); Siune Ambarian (Yerevan, AM); Michael F. Goldberg (Brookline, MA)
Assignee: BostonGene Corporation
G16H50/50G16B25/10G16H20/10
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Quick Facts
Patent No.
US 12,462,941
App. No.
18/634,443
Granted
Nov 4, 2025
Kind
B2
Abstract

Aspects of the disclosure relate to methods, systems, and computer-readable storage media that are useful for characterizing subjects having certain cancers, for example cancers typified by solid tumors. The disclosure is based, in part, on methods for determining a tumor microenvironment (TME) type of a cancer subject and determining the subject's prognosis and/or likelihood of responding to one or more therapies based upon the TME type determination.

Claims (259)

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.

2 . The method of claim 1 , wherein obtaining the RNA expression data comprises obtaining RNA expression data indicating RNA expression levels for at least four genes in each of at least two gene groups of the set of gene groups, for between at least three genes and ten genes in each of at least two gene groups of the set of gene groups, or for each gene in each of at least two gene groups of the set of gene groups.

3 . The method of claim 1 , wherein obtaining the RNA expression data further comprises obtaining RNA expression data indicating RNA expression levels for at least three genes in each of at least two gene groups of additional gene groups, for at least four genes in each of at least two gene groups of the additional gene groups, for between at least three genes and ten genes in each of at least two gene groups of the additional gene groups, for each gene in each of at least two gene groups of the additional gene groups, or for each gene in the additional gene groups, the additional gene groups including:

(a) Major histocompatibility complex class II cells (MHC II) group: HLA-DRB1, HLA-DMA, HLA-DRA, HLA-DQB1, CIITA, HLA-DPB1, HLA-DMB, HLA-DQA1, and HLA-DPA1;

(b) NK cells group: GNLY, KLRK1, KLRF1, GZMH, NCR3, EOMES, NCR1, SH2D1B, IFNG, CD226, FGFBP2, KLRC2, GZMB, KIR2DL4, NKG7, CD244, and CD160;

(c) B cells group: PAX5, MS4A1, CD19, CR2, TNFRSF13B, TNFRSF13C, TNFRSF17, CD79B, BLK, CD22, CD79A, STAP1, and FCRL5;

(d) CD8 T cells group: KLRK1, CD8B, CD8A, PRF1, EOMES, TRAT1, GZMB, GZMA, GZMK, ZAP70, NKG7, and TBX21;

(e) Proliferation rate group: CETN3, CCNB1, CCND1, CCNE1, MCM6, PLK1, CDK2, AURKB, ESCO2, AURKA, MCM2, MKI67, E2F1, BUB1, and MYBL2;

(f) T cells group: ITK, CD3G, CD3D, TRBC1, CD3E, TRAT1, TRAC, TRBC2, CD28, CD5, and TBX21;

(g) Regulatory T (Treg) cells group: CCR8, TNFRSF18, FOXP3, IKZF2, CTLA4, IKZF4, and IL2RA;

(h) Matrix group: VTN, ELN, COL11A1, COL4A1, TNC, COL1A1, COL1A2, COL3A1, LAMA3, LGALS9, FN1, COL5A1, LAMB3, LGALS7, and LAMC2;

(i) Matrix remodeling group: LOX, MMP12, MMP9, PLOD2, ADAMTS5, MMP3, ADAMTS4, MMP11, MMP1, CA9, MMP2, and MMP7; and

(j) Angiogenesis group: VEGFA, TEK, PDGFC, VWF, CXCR2, ANGPT1, FLT1, KDR, ANGPT2, VEGFB, VEGFC, PGF, and CDH5.

4 . The method of claim 1 , wherein generating the TME signature further comprises generating, for at least a subset of signaling types, one or more signaling pathway activity scores using the RNA expression levels, the signaling types including:

(a) EGFR signaling;

(b) Hypoxia signaling;

(c) MAPK signaling;

(d) PI3K signaling;

(e) TGF-β signaling; and

(f) Trail signaling.

5 . The method of claim 1 , wherein determining the gene group score comprises:

(i) determining a respective gene group score for each of at least two of the following gene groups, using, for a particular gene group, RNA expression levels for at least three genes in the particular gene group to determine the gene group score for the particular gene group, or

(ii) determining a respective gene group score for each of the following gene groups, using, for a particular gene group, RNA expression levels for each gene in each gene group to determine the gene group score for each particular gene group,

the gene groups including:

(a) Major histocompatibility complex class II cells (MHC II) group: HLA-DRB1, HLA-DMA, HLA-DRA, HLA-DQB1, CIITA, HLA-DPB1, HLA-DMB, HLA-DQA1, and HLA-DPA1;

(b) NK cells group: GNLY, KLRK1, KLRF1, GZMH, NCR3, EOMES, NCR1, SH2D1B, IFNG, CD226, FGFBP2, KLRC2, GZMB, KIR2DL4, NKG7, CD244, and CD160;

(c) B cells group: PAX5, MS4A1, CD19, CR2, TNFRSF13B, TNFRSF13C, TNFRSF17, CD79B, BLK, CD22, CD79A, STAP1, and FCRL5;

(d) CD8 T cells group: KLRK1, CD8B, CD8A, PRF1, EOMES, TRAT1, GZMB, GZMA, GZMK, ZAP70, NKG7, and TBX21;

(e) cDC1 group: XCR1, CLEC9A, Clorf54, BATF3, WDFY4, and HLA-DOB;

(f) cDC2 group: ITGAX, HLA-DRA, HLA-DRB1, CD1C, FCER1A, CLEC10A, and AMICA1;

(g) pDC group: IL3RA, CLEC4C, CCR2, CXCR3, GZMB, DERL3, LILRA4, and SCT;

(h) Proliferation rate group: CETN3, CCNB1, CCND1, CCNE1, MCM6, PLK1, CDK2, AURKB, ESCO2, AURKA, MCM2, MKI67, E2F1, BUB1, and MYBL2;

(i) T cells group: ITK, CD3G, CD3D, TRBC1, CD3E, TRAT1, TRAC, TRBC2, CD28, CD5, and TBX21;

(j) M1 cytokines group: CXCL10, IL23A, IL1B, IL12B, TNF, and CXCL9;

(k) Panmacrophage signature group: C1QC, CSF1R, CD163, SIGLEC1, C1QA, VSIG4, MSR1, and CD68;

(l) TLS group: CXCL10, SELL, LAMP3, FDCSP, CD86, CXCL13, PTPRCAP, CCR7, LTA, CXCR3, CCL21, CCL19, JCHAIN, CXCL9, and TNFRSF17;

(m) Proinflammatory cytokines group: IL23A, IFNB1, IL1A, IL1B, TNF, CXCL2, IL6, IL26, CCL2, CCL4, LIF, and CCL3;

(n) Anti-tumor chemokines group: CXCL10, CXCL9, CXCL13, XCL1, CCL5, CCL21, CCL19, and XCL2;

(o) Pro-tumor chemokines group: CCL26, CXCL6, CCL20, CXCL8, CXCL1, CCL18, CCL17, and CCL22;

(p) Myeloid checkpoints group: PDCD1LG2, HAVCR2, CD274, and C10orf54;

(q) Lymphoid checkpoints group: BTLA, TIGIT, LAG3, PVRIG, PDCD1, and CTLA4;

(r) Cytotoxic cell inactivation group: PIM2, SERPINB9, LGALS9, CD5, KLRB1, FASLG, KLRD1, LAIR1, LAIR2, and SIGLEC7;

(s) Regulatory T (Treg) cells group: CCR8, TNFRSF18, FOXP3, IKZF2, CTLA4, IKZF4, and IL2RA;

(t) Breg group: ZBTB32, NFKBID, SOX5, EBI3, and ZBTB20;

(u) Myeloid suppression group: IL10, FGL2, EBI3, CYBB, IL4I1, TGFBI, IDO1, PTGS2, and MSR1;

(v) Phagocytosis inhibition group: LILRB3, LILRB1, FCGR2B, LILRB4, SIRPA, SIGLEC10, LILRB2, PECAM1, CD300A, CD300LF, and CD33;

(w) Stromal suppression group: IL11, TGFB2, TDO2, TSLP, IL6, TGFB3, and TGFBI;

(x) Exclusion group: GAS6, VEGFA, PDGFC, FGF2, EDNRB, TNFAIP6, and CXCL12;

(y) Matrix group: VTN, ELN, COL11A1, COL4A1, TNC, COL1A1, COL1A2, COL3A1, LAMA3, LGALS9, FN1, COL5A1, LAMB3, LGALS7, and LAMC2;

(z) Endothelium group: ECSCR, NOS3, MMRN1, VWF, CLEC14A, FLT1, KDR, ROBO4, ENG, CDH5, and MMRN2;

(aa) 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;

(ab) Matrix remodeling group: LOX, MMP12, MMP9, PLOD2, ADAMTS5, MMP3, ADAMTS4, MMP11, MMP1, CA9, MMP2, and MMP7;

(ac) Angiogenesis group: VEGFA, TEK, PDGFC, VWF, CXCR2, ANGPT1, FLT1, KDR, ANGPT2, VEGFB, VEGFC, PGF, and CDH5;

(ad) EMT signature group: RUNX2, FOXM1, SNAI1, TWIST1, and SNAI2;

(ae) Adipocytes group: GPD1, LBP, PTGER3, DLAT, FABP4, LEP, PLIN1, ADIPOQ, PPP1R1A, ADH1B, LIPE, and COL4A4;

(af) Metastasis signature group: MMP9, HPSE, PARP1, CDH2, RCC2, and SERPINH1;

(ag) Metabolic suppression of CTL group: SPHK1, MSR1, ADORA2A, and ENTPD1;

(ah) Hypoxia factors group: LOX, FUT11, PGK1, CA12, TPI1, PDK1, EPAS1, LDHA, SLC2A1, PFKFB3, P4HA1, ALDOA, CA9, HK2, and NDRG1;

(ai) Autophagy group: ATG12, ATG9A, TFEB, RB1CC1, MAP1LC3B, GABARAPL2, ATG4B, ATG7, GABARAP, VMP1, ATG14, GABARAPL1, ATG13, and NBR1;

(aj) Acidosis group: SLC16A1, SLC16A4, MAPK14, and SLC9A1;

(ak) 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;

(al) Apoptosis group: BCL10, BIK, CASP6, TNFRSF12A, CASP2, CASP3, CASP7, CASP8, CYLD, FAS, IER3, PMAIP1, BCL2L11, TNFRSF10A, TNFRSF10B, APAF1, XAF1, and CASP8AP2; and

(am) Glycolysis group: ALDOA, TPI1, GPD2, PGK1, LDHA, PFKP, BPGM, ENO1, GPI, and SLC16A3.

6 . The method of claim 1 , wherein determining the gene group score comprises determining a first score of a first gene group using:

(i) a single-sample Gene Set Enrichment Analysis (ssGSEA) technique to determine the gene group score from RNA expression levels for at least some of the genes in one or the following gene groups, or

(ii) an ssGSEA technique to determine the gene group score from RNA expression levels for each of the genes in each of the following gene groups,

the gene groups comprising:

(a) Major histocompatibility complex class II cells (MHC II) group: HLA-DRB1, HLA-DMA, HLA-DRA, HLA-DQB1, CIITA, HLA-DPB1, HLA-DMB, HLA-DQA1, and HLA-DPA1;

(b) NK cells group: GNLY, KLRK1, KLRF1, GZMH, NCR3, EOMES, NCR1, SH2D1B, IFNG, CD226, FGFBP2, KLRC2, GZMB, KIR2DL4, NKG7, CD244, and CD160;

(c) B cells group: PAX5, MS4A1, CD19, CR2, TNFRSF13B, TNFRSF13C, TNFRSF17, CD79B, BLK, CD22, CD79A, STAP1, and FCRL5;

(d) CD8 T cells group: KLRK1, CD8B, CD8A, PRF1, EOMES, TRAT1, GZMB, GZMA, GZMK, ZAP70, NKG7, and TBX21;

(e) cDC1 group: XCR1, CLEC9A, Clorf54, BATF3, WDFY4, and HLA-DOB;

(f) cDC2 group: ITGAX, HLA-DRA, HLA-DRB1, CD1C, FCER1A, CLEC10A, and AMICA1;

(g) pDC group: IL3RA, CLEC4C, CCR2, CXCR3, GZMB, DERL3, LILRA4, and SCT;

(h) Proliferation rate group: CETN3, CCNB1, CCND1, CCNE1, MCM6, PLK1, CDK2, AURKB, ESCO2, AURKA, MCM2, MKI67, E2F1, BUB1, and MYBL2;

(i) T cells group: ITK, CD3G, CD3D, TRBC1, CD3E, TRAT1, TRAC, TRBC2, CD28, CD5, and TBX21;

(j) M1 cytokines group: CXCL10, IL23A, IL1B, IL12B, TNF, and CXCL9;

(k) Panmacrophage signature group: C1QC, CSF1R, CD163, SIGLEC1, C1QA, VSIG4, MSR1, and CD68;

(l) TLS group: CXCL10, SELL, LAMP3, FDCSP, CD86, CXCL13, PTPRCAP, CCR7, LTA, CXCR3, CCL21, CCL19, JCHAIN, CXCL9, and TNFRSF17;

(m) Proinflammatory cytokines group: IL23A, IFNB1, IL1A, IL1B, TNF, CXCL2, IL6, IL26, CCL2, CCL4, LIF, and CCL3;

(n) Anti-tumor chemokines group: CXCL10, CXCL9, CXCL13, XCL1, CCL5, CCL21, CCL19, and XCL2;

(o) Pro-tumor chemokines group: CCL26, CXCL6, CCL20, CXCL8, CXCL1, CCL18, CCL17, and CCL22;

(p) Myeloid checkpoints group: PDCD1LG2, HAVCR2, CD274, and C10orf54;

(q) Lymphoid checkpoints group: BTLA, TIGIT, LAG3, PVRIG, PDCD1, and CTLA4;

(r) Cytotoxic cell inactivation group: PIM2, SERPINB9, LGALS9, CD5, KLRB1, FASLG, KLRD1, LAIR1, LAIR2, and SIGLEC7;

(s) Regulatory T (Treg) cells group: CCR8, TNFRSF18, FOXP3, IKZF2, CTLA4, IKZF4, and IL2RA;

(t) Breg group: ZBTB32, NFKBID, SOX5, EBI3, and ZBTB20;

(u) Myeloid suppression group: IL10, FGL2, EBI3, CYBB, IL4I1, TGFBI, IDO1, PTGS2, and MSR1;

(v) Phagocytosis inhibition group: LILRB3, LILRB1, FCGR2B, LILRB4, SIRPA, SIGLEC10, LILRB2, PECAM1, CD300A, CD300LF, and CD33;

(w) Stromal suppression group: IL11, TGFB2, TDO2, TSLP, IL6, TGFB3, and TGFBI;

(x) Exclusion group: GAS6, VEGFA, PDGFC, FGF2, EDNRB, TNFAIP6, and CXCL12;

(y) Matrix group: VTN, ELN, COL11A1, COL4A1, TNC, COL1A1, COL1A2, COL3A1, LAMA3, LGALS9, FN1, COL5A1, LAMB3, LGALS7, and LAMC2;

(z) Endothelium group: ECSCR, NOS3, MMRN1, VWF, CLEC14A, FLT1, KDR, ROBO4, ENG, CDH5, and MMRN2;

(aa) 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;

(ab) Matrix remodeling group: LOX, MMP12, MMP9, PLOD2, ADAMTS5, MMP3, ADAMTS4, MMP11, MMP1, CA9, MMP2, and MMP7;

(ac) Angiogenesis group: VEGFA, TEK, PDGFC, VWF, CXCR2, ANGPT1, FLT1, KDR, ANGPT2, VEGFB, VEGFC, PGF, and CDH5;

(ad) EMT signature group: RUNX2, FOXM1, SNAI1, TWIST1, and SNAI2;

(ae) Adipocytes group: GPD1, LBP, PTGER3, DLAT, FABP4, LEP, PLIN1, ADIPOQ, PPP1R1A, ADH1B, LIPE, and COL4A4;

(af) Metastasis signature group: MMP9, HPSE, PARP1, CDH2, RCC2, and SERPINH1;

(ag) Metabolic suppression of CTL group: SPHK1, MSR1, ADORA2A, and ENTPD1;

(ah) Hypoxia factors group: LOX, FUT11, PGK1, CA12, TPI1, PDK1, EPAS1, LDHA, SLC2A1, PFKFB3, P4HA1, ALDOA, CA9, HK2, and NDRG1;

(ai) Autophagy group: ATG12, ATG9A, TFEB, RB1CC1, MAP1LC3B, GABARAPL2, ATG4B, ATG7, GABARAP, VMP1, ATG14, GABARAPL1, ATG13, and NBR1;

(aj) Acidosis group: SLC16A1, SLC16A4, MAPK14, and SLC9A1;

(ak) 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;

(al) Apoptosis group: BCL10, BIK, CASP6, TNFRSF12A, CASP2, CASP3, CASP7, CASP8, CYLD, FAS, IER3, PMAIP1, BCL2L11, TNFRSF10A, TNFRSF10B, APAF1, XAF1, and CASP8AP2; and

(am) Glycolysis group: ALDOA, TPI1, GPD2, PGK1, LDHA, PFKP, BPGM, ENO1, GPI, and SLC16A3.

7 . The method of claim 1 , wherein generating the TME signature further comprises normalizing the gene group score, wherein the normalizing comprises applying median scaling to the gene group score.

8 . The method of claim 1 ,

wherein the plurality of TME types is associated with a respective plurality of TME signature clusters,

wherein identifying, using the TME signature and from among a plurality of TME types, the TME type for the subject comprises:

associating the TME signature of the subject with a particular one of the plurality of TME signature clusters; and

identifying the TME type for the subject as the TME type corresponding to the particular one of the plurality of TME signature clusters to which the TME signature of the subject is associated.

9 . The method of claim 8 , further comprising generating the plurality of TME signature clusters, the generating comprising:

obtaining multiple sets of RNA expression data by sequencing biological samples from multiple respective subjects, each of the multiple sets of RNA expression data indicating RNA expression levels for at least some genes in each of the at least some of the plurality of the set of gene groups; and

generating multiple TME signatures from the multiple sets of RNA expression data, each of the multiple TME signatures comprising gene group expression scores for respective gene groups in the plurality of gene groups, the generating comprising, for each particular one of the multiple TME signatures:

determining the TME signature by determining the gene group expression scores using the RNA expression levels in the particular set of RNA expression data for which the particular one TME signature is being generated; and

clustering the multiple TME signatures to obtain the plurality of TME signature clusters.

10 . The method of claim 8 , further comprising:

updating the plurality of TME signature clusters using the TME signature of the subject, wherein the TME signature of the subject is one of a threshold number TME signatures for a threshold number of subjects, wherein when the threshold number of TME signatures is generated the TME signature clusters are updated,

wherein the threshold number of TME signatures is at least 50, at least 75, at least 100, at least 200, at least 500, at least 1000, or at least 5000 TME signatures.

11 . The method of claim 10 , wherein the updating is performed using a clustering algorithm selected from the group consisting of a dense clustering algorithm, spectral clustering algorithm, k-means clustering algorithm, hierarchical clustering algorithm, and an agglomerative clustering algorithm.

12 . The method of claim 10 , further comprising:

determining a TME type of a second subject, wherein the TME type of the second subject is identified using the updated TME signature clusters, wherein the identifying comprises:

determining a TME signature of the second subject from RNA expression data obtained by sequencing a biological sample obtained from the second subject;

associating the TME signature of the second subject with a particular one of the plurality of the updated TME signature clusters; and

identifying the TME type for the second subject as the TME type corresponding to the particular one of the plurality of updated TME signature clusters to which the TME signature of the second subject is associated.

13 . The method of claim 1 , wherein the plurality of TME types comprises: Lymphoid-Cell Enriched (IE/L) type; B-Cell Enriched, Angiogenic (IE/B/A) type; Immune-Enriched, Hypoxic (IE/H) type; Highly Immune-Enriched, Inflamed (IE/Inf) type; Immune-Enriched, Fibrotic (IE/F) type; Fibrotic, Angiogenic, Myeloid (F/A/M) type; Fibrotic, Hypoxic (F/H) type; Immune Desert (D) type; and/or Faintly Infiltrated, Angiogenic (D/A) type.

14 . The method of claim 13 , wherein:

the Lymphoid-Cell Enriched (IE/L) type is associated with lymphoid-cell-enriched, non-stroma-enriched, myeloid cell deficient, and moderate tumor proliferation rate biological samples,

the B-Cell Enriched, Angiogenic (IE/B/A) type is associated with lymphoid-cell-enriched, myeloid-cell-enriched, adipocyte-enriched, and low tumor proliferation rate biological samples,

the Immune-Enriched, Hypoxic (IE/H) type is associated with lymphoid-cell-enriched, myeloid-cell-enriched, hypoxic, glycolytic, EGFR and MAPK upregulated, and high tumor proliferation rate biological samples,

the Highly Immune-Enriched, Inflamed (IE/Inf) type is associated with lymphoid-cell-enriched, myeloid-cell-enriched, inflamed, non-stroma-enriched, and low tumor proliferation rate biological samples,

the Immune-Enriched, Fibrotic (IE/F) type is associated with myeloid-cell-enriched, stroma-enriched, angiogenetic, TGF-β upregulated, and low tumor proliferation rate biological samples, the Fibrotic, Angiogenic, Myeloid (F/A/M) type is associated with stroma-enriched, myeloid cell deficient, TGF-β, EGFR, and MAPK upregulated, and hypoxic biological samples,

the Fibrotic, Hypoxic (F/H) type is associated with hypoxic, tumor-cell-enriched, TGF-β, EGFR, MAPK, and PI3K upregulated, and high tumor proliferation rate biological samples,

the Immune Desert (D) type is associated with tumor-cell-enriched, lymphoid cell deficient, mildly hypoxic, and high tumor proliferation rate biological samples, and/or

the Faintly Infiltrated, Angiogenic (D/A) type is associated with tumor-cell-enriched, angiogenic, TGF-β upregulated, and low tumor proliferation rate biological samples.

15 . The method of claim 1 , wherein the plurality of TME types was generated by:

determining a plurality of TME signatures for a respective plurality of subjects using RNA expression data from biological samples obtained from the plurality of subjects, each of the plurality of TME signatures containing a gene group expression level for at least some of the set of gene groups; and

clustering the plurality of TME signatures to obtain the TME types.

16 . The method of claim 1 , wherein the at least one therapeutic agent comprises an immuno-oncology (IO) agent, optionally wherein the IO agent comprises an immune checkpoint inhibitor or a tyrosine kinase inhibitor (TKI).

17 . The method of claim 16 , wherein the immune checkpoint inhibitor comprises an anti-TGF-β antibody, an anti-PDGFR antibody, an anti-PD-1 antibody, an anti-LAG3 antibody, an anti-PD-L1 antibody, an anti-IL-6 antibody, an anti-CD276 antibody, an anti-PD-L2 antibody, an anti-SIRPa antibody, an anti-VISTA antibody, an anti-TIGIT antibody, an anti-CTLA4 antibody, or an anti-PVRIG antibody.

18 . 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-PD-L2 antibody or anti-SIRPa antibody as the at least one therapeutic agent when the subject is identified as having a Fibrotic, Angiogenic, Myeloid (F/A/M) or Immune-Enriched, Fibrotic (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 Highly Immune-Enriched, Inflamed (IE/Inf) type TME type.

19 . 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-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.

Assignments (6)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2025
From: SAVCHENKO, MARIA; LUKASHEVICH, NADEZHDA; AMBARIAN, SIUNE
To: BOSTONGENE TECHNOLOGIES, LLC
Reel/Frame 071358/0710 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2025
From: BOSTONGENE TECHNOLOGIES, LLC
To: BOSTONGENE CORPORATION
Reel/Frame 071358/0937 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2025
From: GOLDBERG, MICHAEL F.
To: BOSTONGENE CORPORATION
Reel/Frame 071359/0007 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2024
From: KUST, SOFYA; ZOTOVA, ANASTASIA; OCHEREDKO, ELENA
To: BOSTONGENE TECHNOLOGIES, LLC
Reel/Frame 067848/0976 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2024
From: BOSTONGENE TECHNOLOGIES, LLC
To: BOSTONGENE CORPORATION
Reel/Frame 067848/0984 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2024
From: BAGAEV, ALEXANDER
To: BOSTONGENE CORPORATION
Reel/Frame 067848/0990 →
Continuity (4)
Provisional Application 63627483 · Jan 31, 2024
Provisional Application 63465991 · May 12, 2023
Provisional Application 63459232 · Apr 13, 2023
Related Publication 20240347211A1 · Oct 17, 2024
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