Table 1.
Studies applying computational tools to investigate the immune landscape of tumors classified based on hypoxia signatures.
| s.n | Cancer | Hypoxia Signature | Cohort Number‡ | Immune Investigation Method | High-Risk Group (Hypoxia-High) | Low-Risk Group (Hypoxia-Low) | Reference |
|---|---|---|---|---|---|---|---|
| 1 | ACC* | 3 genes (CCNA2, COL5A1, EFNA3) | 1 | CIBERSORT | Resting NK cell | Activated NK cell | (211) |
| 2 | BLCA | 8 genes (AKAP12, ALDOB, CASP6, DTNA, HS3ST1, JUN, KDELR3, STC1) | 3 | CIBERSORT | M0 and M1 macrophages | (189) | |
| 3 | BLCA# | 4 genes (ANXA2, COL5A1, GALK1, HS3ST1) | 1 | ESTIMATE; ssGSEA | Immune and stromal scores positively correlated with risk score | (212) | |
| Activated CD4 T cell, activated CD8 T cell, central memory CD8 T cell, effector memory CD8 T cell, gamma delta T cell, follicular helper T cell, Th1, Th2, aDC, pDC, activated B cell, immature B cell, memory B cell, NK cell, NK T cell, Treg, macrophage, MDSC, mast cell, monocyte, neutrophil, eosinophil | Th17, CD56bright NK cell | ||||||
| 4 | BLCA# | 16 genes (AKAP12, ANKZF1, CASP6, CCNG2, GALK1, GAPDH, HDLBP, HEXA, HS3ST1, SDC4, SLC2A1, SLC2A3, SRPX, STC1, VEGFA, WISP2) | 2 | ssGSEA | CD8 T cell, NK cell, DC, Th1 | (190) | |
| Risk score positively related to T cell inflamed score and enrichment scores of immunotherapy-positive gene signatures | |||||||
| 5 | BLCA# | 7 genes (ALDOB, EGFR, FOXO3, GPC1, SDC4, SLC2A3, VEGFA) | 1 | CIBERSORT | Resting mast cell, neutrophil, resting CD4 memory T cell | Follicular helper T cell, CD8 T cell, plasma cell | (213) |
| 6 | BC | 13 genes (ADM, ALDOA, CDKN3, LDHA, MIF, MRPS17, NDRG1, P4HA1, PGAM1, SLC2A1, TPI1, TUBB6, VEGFA) | 1 | ImmuCellAI | nTreg cell, iTreg cell | CD8 T cell, CD4 T cell | (214) |
| 7 | CRC | 5 genes (ARL4C, CARS2, PSMD12, PTTG1IP, SEC61G) | 1 | GSEA; ESTIMATE | Enriched immune pathways | (215) | |
| Positively correlated with immune score and stromal score | |||||||
| 8 | CRC | 12 genes (CASP6, CYB5R3, DTX3L, FAM117B, IRF1, MBTD1, MINPP1, ORAI3, TNFAIP8, TRAF3, PRELID2, ZBTB44) | 2 | ESTIMATE; CIBERSORT | Treg, M2 macrophage | Higher immune and stromal scores; CD4 T cell, M1 macrophage | (216) |
| 9 | CRC | 4 genes (ALDOB, ALDOC, GPC1, SLC2A3) | 2 | CIBERSORT | M0 macrophage | (217) | |
| 10 | CRC | 356 genes | 4 | CIBERSORT | M0 and M2 macrophages | CD8 T cell, resting NK, resting CD4 memory T cell | (191) |
| 11 | GC# | 2 genes (EFNA3, SERPINE1) | 2 | ESTIMATE; ssGSEA | Higher immune and stromal scores; Treg, macrophage, neutrophil, mast cell | (192) | |
| 12 | Glioma# | 5 genes (GAPDH, HK2, JUN, LDHA, VEGFA) | 2 | CIBERSORT | Resting CD4 memory T cell, Treg, resting NK cell, M0 macrophage, neutrophil | (193) | |
| 13 | HNSCC | 24 genes (AMPD3, BHLHE40, COL5A1, CP, CSRP2, CXCR4, DDIT4, DUSP1, ERRFI1, F3, GPC4, HS3ST1, IL6, ISG20, MAFF, PGM2, PIM1, PLAC8, PPP1R3C, S100A4, SDC2, SELENBP1, SERPINE1, SRPX) | 1 | CIBERSORT | Activated DC, M0 macrophage, eosinophil, activated mast cell, resting NK cell, resting CD4 memory T cell | Memory B cell, CD8 T cell, resting mast cell, Treg, follicular helper T cell, activated CD4 memory T cell, gamma delta T cell, plasma cell, activated NK cell | (218) |
| 14 | HCC | 4 genes (ENO1, GAPDH, LDHA, SLC2A1) | 1 | ESTIMATE CIBERSORT | Higher immune score; Treg, M0 macrophage, neutrophil | Activated NK cell, M1 macrophage, resting mast cell | (219) |
| 15 | HCC# | 24 genes (ACOT7, ADM, ALDOA, ANGPTL4, BNC1, CA9, CDKN3, COL4A6, ENO1, FOSL1, GNAI1, LDHA, MIF, MRPS17, NDRG1, P4HA1, PGAM1, PGK1, SDC1, SLC16A1, SLC2A1, TPI1, TUBB6, VEGFA) | 1 meta-cohort (from 3 datasets) | MCP-counter; ssGSEA; TIDE | CD4 T cell, activated CD8 T cell, iDC, aDC, CD56bright and CD56dim NK cell, gamma delta T cell, immature B cell, macrophage, mast cell, MDSC, NK T cell, pDC, follicular helper T cell, Th1, Th2; Three times higher response to ICI | Eosinophil, neutrophil, Treg, Th17 | (220) |
| 16 | HCC# | 21 genes (ADM, BNIP3, BNIP3L, CA9, EGLN3, GDF15, GYS1, HCAR3, HILPDA, HK2, INSIG2, JUN, KDM3A, PFKFB4, PLIN2, PTPRH, SLC2A3, SMAD3, SPAG4, TMEM45A, WSB1) | 11 | ESTIMATE; CIBERSORT | 3 cohorts: higher stromal score; 6 cohorts: higher immune score; 6 cohorts: activated CD4 memory T cell; 5 cohorts: activated mast cell; 5 cohorts: M0 macrophage | 6 cohorts: resting CD4 memory T cell; 5 cohorts: resting mast cell; 3 cohorts: NK cell | (194) |
| 17 | HCC# | 3 genes (CDCA8, PDSS1, SLC7A11) | 1 | CIBERSORT | M0 macrophage, memory B cell, follicular helper T cell | (221) | |
| 18 | HCC | 10 genes (APEX1, ATR, CTSA, DNAJC5, ENO1, EPO, HMOX1, LDHA, NDRG1, PER1) | 1 | CIBERSORT | M0 macrophage, Treg, neutrophil, eosinophil | Resting mast cell, resting CD4 memory cell, M1 macrophage, monocyte | (222) |
| 19 | HCC | 4 genes (DCN, DDIT4, NDRG1, PRKCA) | 2 | ssGSEA | Activated B cell, activated CD8 T cell, effector memory CD8 T cell, Treg, Th1, CD56bright NK cell, NK cell, NK T cell, eosinophil, macrophage, mast cell, MDSC, monocyte, pDC | (223) | |
| 20 | NSCLC* | 11 genes (AMPD3, DDX11, FANCI, HIF-3α, IDE, LRP8, NOLC1, PAIP1, PDCD2, PSMF1, SNAPC5) | 1 | ESTIMATE; ssGSEA | Higher immune score; DCs, aDCs, iDCs, pDCs, HLA, B cell, mast cell, neutrophil, T helper cell, T cell co-inhibition, T cell co-stimulation, TILs, Type II IFN response | (224) | |
| 21 | NSCLC | 4 genes (ANGPTL4, PFKP, SLC2A1, XPNPEP1) | 2 | CIBERSORT | Activated CD4 memory T cell, resting NK cell, M0 and M1 macrophages | Memory B cell, resting CD4 memory T cell, monocyte, resting DC, resting mast cell | (195) |
| 22 | NSCLC | 18 genes (ADM, BIK, DDIT3, ENO1, EPAS1, FGF3, GAPDH, MIF, NFKB1, PFKP, PGK1, PLAUR, SPP1, STC1, TEK, TFRC, TGFA, XRCC6) | 1 | ssGSEA | Activated CD4 T cell, CD56bright NK cell, memory B cell, Th2 | Activated B cell, activated CD8 T cell, central memory CD4 T cell, effector memory CD8 T cell, eosinophil, immature B cell, iDC, pDCs, macrophage, mast cell, MDSC, monocyte, NK cell, neutrophil, follicular helper T cell, Th1, Th17 | (225) |
| 23 | NSCLC# | 7 lncRNAs (AC010980.2, AC022784.1, AC079949.2, AC090001.1, AL161431.1, LINC00707, LINC00941) | 1 | CIBERSORT | Neutrophil, M0 and M2 macrophages | Monocyte | (226) |
| 24 | SKCM | 11 genes (CP, DPYSL4, EGFR, FBP1, FOXO3, IGFBP1, ISG20, KIF5A, PPARGC1A, S100A4, SDC3) | 2 | CIBERSORT | Treg, mast cell; 1 cohort: resting CD4 memory T cell, monocyte | Activated CD4 memory T cell, M1 macrophage; 1 cohort: CD8 T cell, plasma cell | (196) |
| 25 | OSCC# | 4 genes (ALDOA, P4HA1, PGK1, VEGFA) | 1 | CIBERSORT | M0 macrophage, mast cell | Naïve B cell, CD8 T cell, follicular helper T cell, Treg, neutrophil | (227) |
| 26 | OS* | 2 genes (P4HA1, DCN) | 2 | ssGSEA | DC, pDC, macrophage, neutrophil, TIL | (228) | |
| 27 | OS | 4 genes (EFNA1, P4HA1, STC2, MAFF) | 2 | CIBERSORT | Resting CD4 memory T cell | (229) | |
| 28 | OVC# | 9 genes (ALOX5AP, ANXA1, IGFBP2, LAG3, PLK3, SLC1A1, SREBF1, SREBF2, TGFB1) | 1 | CIBERSORT; TIMER | Activated CD4 memory T cell, gamma-delta T cell, activated NK, neutrophil, M1 and M2 macrophages | Resting CD4 memory T cell, follicular helper T cell, Treg, aDC, resting mast cell; Higher MHC and antigen presenting molecules | (230) |
| 29 | PDAC# | 8 genes (DDIT4, LDHA, MXI1, NDRG1, P4HA1, PGK1, SLC2A1, VEGFA) | 2 | CIBERSORTx | M0 macrophage | CD8 T cell; Higher immune score and cytolytic index§ | (197) |
| 30 | PDAC | 4 genes (ENO3, LDHA, PGK1, PGM1) | 2 | CIBERSORT | M2 macrophage, resting NK cell | CD8 T cell, naive B cell | (231) |
| 31 | RCC | 9 lnRNA (AC002070.1, AC008760.2, AC084876.1, AC147651.1, FOXD2-AS1, ITPR1-DT, LINC00944, LINC01615, LINC02027) | 1 | CIBERSORT | Plasma cell, follicular helper T cell, Treg | M2 macrophage, resting DC, resting mast cell | (232) |
| 32 | RCC | 4 lnRNA (AC026462.3, COMETT, EMX2OS, HAGLR) | 1 | TIMER; ESTIMATE | B cell, CD4 T cell, CD8 T cell, DC, macrophage, neutrophil positively correlated with risk score | (233) | |
| Higher immune and stromal scores | |||||||
| 33 | RCC# | 8 genes (BCL2, KDELR3, KLF6, PCK1, PLAUR, PPARGC1A, RORA, WSB1) | 1 | CIBERSORT | Treg, CD8 T cell, follicular helper T cell, plasma cell, M0 macrophage, activated NK cell | Resting CD4 memory, monocyte, M1 macrophage, resting mast cell, resting NK cell | (234) |
‡Number of independent patient cohorts analyzed with indicated method to investigate immune tumor microenvironment.
#Studies reporting higher immune checkpoint inhibitors or immunosuppressive cytokines or both in High-risk group.
*Studies reporting higher immune checkpoint inhibitors or immunosuppressive cytokines or both in Low-risk group.
§Immune score calculated based on an eighteen gene tumor inflammation signature. The cytolytic index calculated based on the geometric mean of the GZMA (granzyme A) and PRF1 (perforin-1) produced by activated cytolytic CD8+ T cells (197).
s.n, serial number; ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BC, breast cancer; CRC, colorectal cancer; GC, gastric cancer; HNSCC, head and neck squamous cell carcinoma; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; SKCM, skin cutaneous melanoma; OSCC, oral squamous cell carcinoma; OS, osteosarcoma; OVC, ovarian carcinoma; PDAC, pancreatic ductal adenocarcinoma; RCC, renal cell carcinoma; lnRNA, long non-coding RNA; CIBERSORT, Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts; ESTIMATE, Estimation of STromal and Immune cells in MAlignant Tumours using Expression data; GSEA, gene set enrichment analysis; ssGSEA, single-sample GSEA; MCP-counter, Microenvironment Cell Populations-counter; TIMER, Tumor IMmune Estimation Resource; ImmuCellAI, Immune Cell Abundance Identifier; DC, dendritic cell; aDC, activated DC; iDC, immature DC; pDC, plasmacytoid DC; Th1, type 1 T helper cell; Th2, type 2 T helper cell; Th17, T helper 17 cell; Treg, regulatory T cell; iTreg, induced Treg; nTreg, natural Treg; HLA, human leukocyte antigen; TIL, tumor infiltrating leukocytes; IFN, interferon; MHC, major histocompatibility complex.