Intermittent MEK inhibition with GITR costimulation rescues T-cell function for increased efficacy with CTLA-4 blockade in solid tumor models Journal Article
| Authors: | Dong, L.; Choi, H.; Budhu, S.; Schulze, I.; Verma, S.; Mangarin, L. M.; Nevarro, V. E.; Mehanna, N.; Khan, J. F.; Venkatesh, D.; Thach, D.; Rosen, N.; Wolchok, J. D.; Merghoub, T. |
| Article Title: | Intermittent MEK inhibition with GITR costimulation rescues T-cell function for increased efficacy with CTLA-4 blockade in solid tumor models |
| Abstract: | MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway–dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell–mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses. ©2024 American Association for Cancer Research. |
| Keywords: | mitogen activated protein kinase; cancer survival; controlled study; protein expression; unclassified drug; human cell; drug dose reduction; drug efficacy; nonhuman; solid tumor; treatment duration; flow cytometry; neoplasm; neoplasms; cd3 antigen; cd8 antigen; transcription factor foxp3; cd8+ t lymphocyte; cell proliferation; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cell function; glycoprotein gp 100; stat1 protein; cancer immunotherapy; gene expression; tumor volume; mitogen activated protein kinase p38; protein kinase inhibitor; stress activated protein kinase; animal experiment; animal model; colonic neoplasms; antineoplastic activity; pathology; cell line, tumor; phosphatidylinositol 3 kinase; mice, inbred c57bl; c57bl mouse; colorectal carcinoma; pancreas carcinoma; protein kinase inhibitors; disease model; lung tumor; cancer inhibition; granzyme b; regulatory t lymphocyte; immunology; lymphocyte activation; immune response; colon tumor; major histocompatibility antigen class 2; cd4+ t lymphocyte; tumor cell line; tumor cell; single drug dose; immunomodulation; tumor model; cd4 antigen; drug therapy; disease models, animal; adaptive immunity; cytotoxic t lymphocyte antigen 4; hermes antigen; major histocompatibility complex; chemokine receptor ccr7; k ras protein; glucocorticoid induced tumor necrosis factor receptor; cell activation; cd5 antigen; therapy; cd134 antigen; cd28 antigen; lewis carcinoma; cell killing; transcription factor 7; b7 antigen; cd86 antigen; interleukin 2 receptor alpha; lymphoid enhancer factor 1; cell adhesion molecule; major histocompatibility antigen class 1; programmed death 1 ligand 1; inhibitor of differentiation 3; beta actin; high mobility group b1 protein; cd69 antigen; tnfrsf18 protein, mouse; early growth response factor 2; chemokine receptor cxcr3; l selectin; early growth response factor 1; eomesodermin; rantes; selumetinib; interleukin 2 receptor beta; interferon regulatory factor 7; calcyclin; mitogen activated protein kinase kinase inhibitor; immune checkpoint inhibitor; trametinib; long term survival; vinculin; rrm2 protein; glucocorticoid-induced tnfr-related protein; ctla-4 antigen; humans; human; male; female; article; 2 hydroxypropyl beta cyclodextrin; immune checkpoint inhibitors; tcr signaling; antineoplastic monoclonal antibody; tumor necrosis factor receptor superfamily member 9; eomes protein; tox protein; single cell rna seq; ccnb1 protein; transporter associated with antigen processing 1; baculoviral iap repeat containing protein 5; tumor draining lymph node; avutometinib; anti cd8 antibody; anti cytotoxic t lymphocyte antigen 4 antibody; anti glucocorticoid induced tumor necrosis factor receptor antibody; anti ox 40 antibody; bcla2a1b protein; cd200 antigen; cenpa protein; cks1b protein; dapl1 protein; gzma protein; gzmk protein; ifit1 protein; ifit3 protein; klra7 protein; klrc1 protein; klrd1 protein; klre1 protein; klrk1 protein; lgals1 protein; p70s6k protein; sell protein; stmn1 protein; tagap protein; tigit protein |
| Journal Title: | Cancer Immunology Research |
| Volume: | 12 |
| Issue: | 10 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-10-01 |
| Start Page: | 1392 |
| End Page: | 1408 |
| Language: | English |
| DOI: | 10.1158/2326-6066.Cir-23-0729 |
| PUBMED: | 38885362 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
