IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation
ABSTRACTImmune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of c...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2212673 |
| _version_ | 1797356269536804864 |
|---|---|
| author | John P. Dowling Pavel A. Nikitin Fang Shen Halley Shukla James P. Finn Nirja Patel Cezary Swider Jamie L. Bingaman-Steele Chris Nicolescu Eden L Sikorski Evan J. Greenawalt Michael J. Morin Matthew K. Robinson Karen Lundgren Benjamin C. Harman |
| author_facet | John P. Dowling Pavel A. Nikitin Fang Shen Halley Shukla James P. Finn Nirja Patel Cezary Swider Jamie L. Bingaman-Steele Chris Nicolescu Eden L Sikorski Evan J. Greenawalt Michael J. Morin Matthew K. Robinson Karen Lundgren Benjamin C. Harman |
| author_sort | John P. Dowling |
| collection | DOAJ |
| description | ABSTRACTImmune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo, IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth. |
| first_indexed | 2024-03-08T14:24:11Z |
| format | Article |
| id | doaj.art-687ffc074dce4fcdb4a25e4af9665e76 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-03-08T14:24:11Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-687ffc074dce4fcdb4a25e4af9665e762024-01-13T11:27:51ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2212673IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activationJohn P. Dowling0Pavel A. Nikitin1Fang Shen2Halley Shukla3James P. Finn4Nirja Patel5Cezary Swider6Jamie L. Bingaman-Steele7Chris Nicolescu8Eden L Sikorski9Evan J. Greenawalt10Michael J. Morin11Matthew K. Robinson12Karen Lundgren13Benjamin C. Harman14Research & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAResearch & Development, Immunome Inc, Exton, PA, USAABSTRACTImmune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo, IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth.https://www.tandfonline.com/doi/10.1080/19420862.2023.2212673cancerIL-1 familyIL-38inflammationinnate immunity |
| spellingShingle | John P. Dowling Pavel A. Nikitin Fang Shen Halley Shukla James P. Finn Nirja Patel Cezary Swider Jamie L. Bingaman-Steele Chris Nicolescu Eden L Sikorski Evan J. Greenawalt Michael J. Morin Matthew K. Robinson Karen Lundgren Benjamin C. Harman IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation mAbs cancer IL-1 family IL-38 inflammation innate immunity |
| title | IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation |
| title_full | IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation |
| title_fullStr | IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation |
| title_full_unstemmed | IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation |
| title_short | IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation |
| title_sort | il 38 blockade induces anti tumor immunity by abrogating tumor mediated suppression of early immune activation |
| topic | cancer IL-1 family IL-38 inflammation innate immunity |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2212673 |
| work_keys_str_mv | AT johnpdowling il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT pavelanikitin il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT fangshen il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT halleyshukla il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT jamespfinn il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT nirjapatel il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT cezaryswider il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT jamielbingamansteele il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT chrisnicolescu il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT edenlsikorski il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT evanjgreenawalt il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT michaeljmorin il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT matthewkrobinson il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT karenlundgren il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation AT benjamincharman il38blockadeinducesantitumorimmunitybyabrogatingtumormediatedsuppressionofearlyimmuneactivation |