IGSF8 is an innate immune checkpoint and cancer immunotherapy target.
Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.
Pubmed ID: 38657602 RIS Download
Research resources used in this publication
- psPAX2 (RRID:Addgene_12260) (plasmid)
- CT26.WT (RRID:CVCL_7256) (cell line)
- pMD2.G (RRID:Addgene_12259) (plasmid)
- lentiCas9-Blast (RRID:Addgene_52962) (plasmid)
- LL/2 (LLC1) (RRID:CVCL_4358) (cell line)
- lentiGuide-Puro (RRID:Addgene_52963) (plasmid)
- B16-F10 (RRID:CVCL_0159) (cell line)
- lentiCRISPR v2 (RRID:Addgene_52961) (plasmid)
- NCI-H520 (RRID:CVCL_1566) (cell line)
- EMT6 (RRID:CVCL_1923) (cell line)
- A-375 (RRID:CVCL_0132) (cell line)
- VMM17 (RRID:CVCL_S581) (cell line)
- K-562 (RRID:CVCL_0004) (cell line)
- AGS (RRID:CVCL_0139) (cell line)
- COLO 205 (RRID:CVCL_0218) (cell line)
- GraphPad Prism (RRID:SCR_002798) (software resource)
- FlowJo (RRID:SCR_008520) (software resource)
- Kaluza (RRID:SCR_016182) (software resource)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- APC anti-mouse CD19 (RRID:AB_313647)
- FITC anti-rat CD90/mouse CD90.1 (Thy-1.1) (RRID:AB_1595653)
- mouse anti-rabbit IgG-PE (RRID:AB_628498)
- F(ab')2-Goat anti-Mouse IgG (H+L) Secondary Antibody, PE, eBioscience (RRID:AB_11063706)
- Mouse IgG1 kappa Isotype Control (P3.6.2.8.1), PerCP-eFluor™ 710, eBioscience (RRID:AB_1834453)
- Mouse IgG1 kappa Isotype Control (P3.6.2.8.1), FITC, eBioscience (RRID:AB_10596964)
- InVivoPlus mouse IgG2a isotype control (RRID:AB_1107771)
- InVivoPlus anti-mouse PD-1 (CD279) (RRID:AB_2687796)
- Ly-49I Monoclonal Antibody (YLI-90), PE, eBioscience (RRID:AB_466021)
- InVivoMab anti-mouse CD4 (RRID:AB_10950382)
- InVivoMab anti-mouse CD8β (Lyt 3.2) (RRID:AB_2687706)
- InVivoPlus anti-mouse NK1.1 (RRID:AB_1107737)
- InVivoPlus mouse IgG1 isotype control, unknown specificity (RRID:AB_1107784)
- Alexa Fluor(R) 700 anti-mouse CD4 (RRID:AB_493699)
- FITC anti-mouse CD11c (RRID:AB_313775)
- Brilliant Violet 605(TM) anti-mouse CD11c (RRID:AB_2562415)
- PE anti-mouse CD11c (RRID:AB_313777)
- PE anti-mouse NK-1.1 (RRID:AB_313395)
- PerCP anti-mouse CD11c (RRID:AB_2129643)
- FITC anti-mouse CD3 (RRID:AB_312661)
- PE/Cyanine7 anti-mouse F4/80 (RRID:AB_893478)
- FITC anti-mouse F4/80 (RRID:AB_893502)
- APC anti-mouse NK-1.1 (RRID:AB_313396)
- PE/Cyanine7 anti-mouse CD19 (RRID:AB_313655)
- PE anti-mouse F4/80 (RRID:AB_893486)
- Pacific Blue(TM) anti-mouse CD19 (RRID:AB_439718)
- Pacific Blue(TM) anti-mouse CD8a (RRID:AB_493425)
- PE/Cyanine7 anti-mouse CD45 (RRID:AB_2860726)
- PerCP/Cyanine5.5 anti-mouse CD45 (RRID:AB_2563538)
- PerCP/Cyanine5.5 anti-mouse/human CD11b (RRID:AB_893232)
- PE/Cyanine7 anti-mouse/human CD11b (RRID:AB_312799)
- APC anti-human CD158e1 (KIR3DL1, NKB1) (RRID:AB_2563360)
- Recombinant Anti-MHC class I + HLA A + HLA B antibody [EPR1394Y] (RRID:AB_3073854)
- InVivoPlus human IgG1 isotype control (RRID:AB_2687817)
- InVivoMab anti-human PD-1 (CD279) (RRID:AB_10950318)
- APC anti-human CD158b/j (KIR2DL2/L3/S2) (RRID:AB_2563377)
- Brilliant Violet 421(TM) anti-human IgG Fc (RRID:AB_2562176)
- APC anti-human Perforin (RRID:AB_2252843)
- PE anti-human CD85j (ILT2) (RRID:AB_2136385)
- PE/Cyanine7 anti-human CD14 (RRID:AB_2566714)
- APC anti-human CD107a (LAMP-1) (RRID:AB_1279055)
- Pacific Blue(TM) anti-human CD8 (RRID:AB_10551438)
- Anti-IGSF8 antibody produced in rabbit (RRID:AB_1851536)
- FITC anti-human CD4 (RRID:AB_314074)
- Anti-pan Cytokeratin (RRID:AB_3086695)
- FITC anti-human IgG Fc (RRID:AB_2721576)
- APC anti-human IgG Fc (RRID:AB_2565790)
- PE anti-human IgG Fc (RRID:AB_2565786)
- Anti-IGSF8 Antibody (RRID:AB_3086693)
- APC anti-human CD56 (NCAM) (RRID:AB_2563913)
- Alexa Fluor(R) 700 anti-human CD56 (NCAM) (RRID:AB_2564099)
- Anti-Beta-2 microglobulin Antibody (APC), Mouse Monoclonal (RRID:AB_3086735)
- PE anti-human CD3 (RRID:AB_314044)
- PE anti-human CD56 (NCAM) (RRID:AB_2563925)
- Human KIR3DL2/CD158k Antibody (RRID:AB_3086694)
- PE anti-human HLA-F (RRID:AB_2650871)
- PE/Dazzle(TM) 594 anti-human HLA-E (RRID:AB_2814258)
- PE anti-human HLA-A,B,C (RRID:AB_314874)
- PE anti-human HLA-G (RRID:AB_1227710)
Associated grants
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This is a list of tools and resources that we have found mentioned in this publication.
APC anti-mouse CD19 (antibody)
RRID:AB_313647
This monoclonal targets CD19
View all literature mentionsFITC anti-rat CD90/mouse CD90.1 (Thy-1.1) (antibody)
RRID:AB_1595653
This monoclonal targets CD90/CD90.1
View all literature mentionsmouse anti-rabbit IgG-PE (antibody)
RRID:AB_628498
This monoclonal targets Rabbit n/a
View all literature mentionsF(ab')2-Goat anti-Mouse IgG (H+L) Secondary Antibody, PE, eBioscience (antibody)
RRID:AB_11063706
This polyclonal secondary targets IgG (H+L)
View all literature mentionsMouse IgG1 kappa Isotype Control (P3.6.2.8.1), PerCP-eFluor™ 710, eBioscience (antibody)
RRID:AB_1834453
This isotype control targets Not Applicable
View all literature mentionsMouse IgG1 kappa Isotype Control (P3.6.2.8.1), FITC, eBioscience (antibody)
RRID:AB_10596964
This isotype control targets Not Applicable
View all literature mentionsInVivoPlus mouse IgG2a isotype control (antibody)
RRID:AB_1107771
This isotype control targets Unknown Specificity
View all literature mentionsInVivoPlus anti-mouse PD-1 (CD279) (antibody)
RRID:AB_2687796
This monoclonal targets PD-1 (CD279)
View all literature mentionsLy-49I Monoclonal Antibody (YLI-90), PE, eBioscience (antibody)
RRID:AB_466021
This monoclonal targets Ly-49I
View all literature mentionsInVivoMab anti-mouse CD4 (antibody)
RRID:AB_10950382
This monoclonal targets CD4
View all literature mentionsInVivoMab anti-mouse CD8β (Lyt 3.2) (antibody)
RRID:AB_2687706
This monoclonal targets CD8β (Lyt 3.2)
View all literature mentionsInVivoPlus anti-mouse NK1.1 (antibody)
RRID:AB_1107737
This monoclonal targets NK1.1
View all literature mentionsInVivoPlus mouse IgG1 isotype control, unknown specificity (antibody)
RRID:AB_1107784
This isotype control targets
View all literature mentionsAlexa Fluor(R) 700 anti-mouse CD4 (antibody)
RRID:AB_493699
This monoclonal targets CD4
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RRID:AB_313775
This monoclonal targets CD11c
View all literature mentionsBrilliant Violet 605(TM) anti-mouse CD11c (antibody)
RRID:AB_2562415
This monoclonal targets CD11c
View all literature mentionsPE anti-mouse CD11c (antibody)
RRID:AB_313777
This monoclonal targets CD11c
View all literature mentionsPE anti-mouse NK-1.1 (antibody)
RRID:AB_313395
This monoclonal targets NK-1.1
View all literature mentionsPerCP anti-mouse CD11c (antibody)
RRID:AB_2129643
This monoclonal targets CD11c
View all literature mentionsFITC anti-mouse CD3 (antibody)
RRID:AB_312661
This monoclonal targets CD3
View all literature mentionsPE/Cyanine7 anti-mouse F4/80 (antibody)
RRID:AB_893478
This monoclonal targets F4/80
View all literature mentionsFITC anti-mouse F4/80 (antibody)
RRID:AB_893502
This monoclonal targets F4/80
View all literature mentionsAPC anti-mouse NK-1.1 (antibody)
RRID:AB_313396
This monoclonal targets NK-1.1
View all literature mentionsPE/Cyanine7 anti-mouse CD19 (antibody)
RRID:AB_313655
This monoclonal targets CD19
View all literature mentionsPE anti-mouse F4/80 (antibody)
RRID:AB_893486
This monoclonal targets F4/80
View all literature mentionsPacific Blue(TM) anti-mouse CD19 (antibody)
RRID:AB_439718
This monoclonal targets CD19
View all literature mentionsPacific Blue(TM) anti-mouse CD8a (antibody)
RRID:AB_493425
This monoclonal targets CD8a
View all literature mentionsPE/Cyanine7 anti-mouse CD45 (antibody)
RRID:AB_2860726
This monoclonal targets CD45
View all literature mentionsPerCP/Cyanine5.5 anti-mouse CD45 (antibody)
RRID:AB_2563538
This monoclonal targets CD45
View all literature mentionsPerCP/Cyanine5.5 anti-mouse/human CD11b (antibody)
RRID:AB_893232
This monoclonal targets CD11b
View all literature mentionsPE/Cyanine7 anti-mouse/human CD11b (antibody)
RRID:AB_312799
This monoclonal targets CD11b
View all literature mentionsAPC anti-human CD158e1 (KIR3DL1, NKB1) (antibody)
RRID:AB_2563360
This monoclonal targets CD158e1
View all literature mentionsRecombinant Anti-MHC class I + HLA A + HLA B antibody [EPR1394Y] (antibody)
RRID:AB_3073854
This recombinant monoclonal targets MHC class I + HLA A + HLA B
View all literature mentionsInVivoPlus human IgG1 isotype control (antibody)
RRID:AB_2687817
This isotype control targets Unknown Specificify
View all literature mentionsInVivoMab anti-human PD-1 (CD279) (antibody)
RRID:AB_10950318
This monoclonal targets PD-1 (CD279)
View all literature mentionsAPC anti-human CD158b/j (KIR2DL2/L3/S2) (antibody)
RRID:AB_2563377
This monoclonal targets CD158b/j
View all literature mentionsBrilliant Violet 421(TM) anti-human IgG Fc (antibody)
RRID:AB_2562176
This monoclonal targets IgG
View all literature mentionsAPC anti-human Perforin (antibody)
RRID:AB_2252843
This monoclonal targets Perforin
View all literature mentionsPE anti-human CD85j (ILT2) (antibody)
RRID:AB_2136385
This monoclonal targets CD85j
View all literature mentionsPE/Cyanine7 anti-human CD14 (antibody)
RRID:AB_2566714
This monoclonal targets CD14
View all literature mentionsAPC anti-human CD107a (LAMP-1) (antibody)
RRID:AB_1279055
This monoclonal targets CD107a
View all literature mentionsPacific Blue(TM) anti-human CD8 (antibody)
RRID:AB_10551438
This monoclonal targets CD8
View all literature mentionsAnti-IGSF8 antibody produced in rabbit (antibody)
RRID:AB_1851536
This unknown targets Human IGSF8
View all literature mentionsFITC anti-human CD4 (antibody)
RRID:AB_314074
This monoclonal targets CD4
View all literature mentionsAnti-pan Cytokeratin (antibody)
RRID:AB_3086695
This monoclonal targets pan Cytokeratin
View all literature mentionsFITC anti-human IgG Fc (antibody)
RRID:AB_2721576
This monoclonal targets IgG Fc
View all literature mentionsAPC anti-human IgG Fc (antibody)
RRID:AB_2565790
This monoclonal targets IgG Fc
View all literature mentionsPE anti-human IgG Fc (antibody)
RRID:AB_2565786
This monoclonal targets IgG Fc
View all literature mentionsAnti-IGSF8 Antibody (antibody)
RRID:AB_3086693
This polyclonal targets IGSF8
View all literature mentionsAPC anti-human CD56 (NCAM) (antibody)
RRID:AB_2563913
This monoclonal targets CD56
View all literature mentionsAlexa Fluor(R) 700 anti-human CD56 (NCAM) (antibody)
RRID:AB_2564099
This monoclonal targets CD56
View all literature mentionsAnti-Beta-2 microglobulin Antibody (APC), Mouse Monoclonal (antibody)
RRID:AB_3086735
This monoclonal targets Beta-2 microglobulin
View all literature mentionsPE anti-human CD3 (antibody)
RRID:AB_314044
This monoclonal targets CD3
View all literature mentionsPE anti-human CD56 (NCAM) (antibody)
RRID:AB_2563925
This monoclonal targets CD56
View all literature mentionsHuman KIR3DL2/CD158k Antibody (antibody)
RRID:AB_3086694
This monoclonal targets KIR3DL2/CD158k
View all literature mentionsPE anti-human HLA-F (antibody)
RRID:AB_2650871
This monoclonal targets HLA-F
View all literature mentionsPE/Dazzle(TM) 594 anti-human HLA-E (antibody)
RRID:AB_2814258
This monoclonal targets HLA-E
View all literature mentionsPE anti-human HLA-A,B,C (antibody)
RRID:AB_314874
This monoclonal targets HLA-A
View all literature mentionsPE anti-human HLA-G (antibody)
RRID:AB_1227710
This monoclonal targets HLA-G
View all literature mentionsCT26.WT (cell line)
RRID:CVCL_7256
Cell line CT26.WT is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsLL/2 (LLC1) (cell line)
RRID:CVCL_4358
Cell line LL/2 (LLC1) is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsB16-F10 (cell line)
RRID:CVCL_0159
Cell line B16-F10 is a Cancer cell line with a species of origin Mus musculus (Mouse)
View all literature mentionsNCI-H520 (cell line)
RRID:CVCL_1566
Cell line NCI-H520 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsEMT6 (cell line)
RRID:CVCL_1923
Cell line EMT6 is a Cancer cell line with a species of origin Mus musculus (Mouse)
View all literature mentionsA-375 (cell line)
RRID:CVCL_0132
Cell line A-375 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsVMM17 (cell line)
RRID:CVCL_S581
Cell line VMM17 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsK-562 (cell line)
RRID:CVCL_0004
Cell line K-562 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsAGS (cell line)
RRID:CVCL_0139
Cell line AGS is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCOLO 205 (cell line)
RRID:CVCL_0218
Cell line COLO 205 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsGraphPad Prism (software resource)
RRID:SCR_002798
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsFlowJo (software resource)
RRID:SCR_008520
Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentionsKaluza (software resource)
RRID:SCR_016182
Flow cytometry analysis software.
View all literature mentions
