| First Author | Vanmeerbeek I | Year | 2024 |
| Journal | Sci Adv | Volume | 10 |
| Issue | 29 | Pages | eadm8660 |
| PubMed ID | 39028818 | Mgi Jnum | J:359148 |
| Mgi Id | MGI:7704684 | Doi | 10.1126/sciadv.adm8660 |
| Citation | Vanmeerbeek I, et al. (2024) Targeting conserved TIM3(+)VISTA(+) tumor-associated macrophages overcomes resistance to cancer immunotherapy. Sci Adv 10(29):eadm8660 |
| abstractText | Despite the success of immunotherapy, overcoming immunoresistance in cancer remains challenging. We identified a unique niche of tumor-associated macrophages (TAMs), coexpressing T cell immunoglobulin and mucin domain-containing 3 (TIM3) and V-domain immunoglobulin suppressor of T cell activation (VISTA), that dominated human and mouse tumors resistant to most of the currently used immunotherapies. TIM3(+)VISTA(+) TAMs were sustained by IL-4-enriching tumors with low (neo)antigenic and T cell-depleted features. TIM3(+)VISTA(+) TAMs showed an anti-inflammatory and protumorigenic phenotype coupled with inability to sense type I interferon (IFN). This was established with cancer cells succumbing to immunogenic cell death (ICD). Dying cancer cells not only triggered autocrine type I IFNs but also exposed HMGB1/VISTA that engaged TIM3/VISTA on TAMs to suppress paracrine IFN-responses. Accordingly, TIM3/VISTA blockade synergized with paclitaxel, an ICD-inducing chemotherapy, to repolarize TIM3(+)VISTA(+) TAMs to proinflammatory TAMs that killed cancer cells via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling. We propose targeting TIM3(+)VISTA(+) TAMs to overcome immunoresistant tumors. |
