PDF(Pubmed)
Abstract：
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.
摘要：
尽管免疫疗法取得了成功,克服癌症中的免疫抗性仍然具有挑战性。我们确定了肿瘤相关巨噬细胞（TAMs）的独特生态位，共表达T细胞免疫球蛋白和含粘蛋白结构域3（TIM3）和T细胞活化的V结构域免疫球蛋白抑制剂（VISTA），占主导地位的人类和小鼠肿瘤对大多数目前使用的免疫疗法具有抗性。TIM3+VISTA+TAM由具有低(新)抗原性和T细胞耗尽特征的富含IL-4的肿瘤维持。TIM3+VISTA+TAM显示抗炎和原瘤表型，同时无法感觉到I型干扰素（IFN）。这是由死于免疫原性细胞死亡(ICD)的癌细胞建立的。死亡的癌细胞不仅触发了自分泌I型IFN，而且还暴露了HMGB1/VISTA，使TAM3/VISTA参与抑制旁分泌IFN反应。因此，TIM3/VISTA阻断与紫杉醇协同作用，诱导ICD的化疗,通过肿瘤坏死因子相关的凋亡诱导配体（TRAIL）信号将TIM3+VISTA+TAMs复极化为可杀死癌细胞的促炎TAMs。我们建议靶向TIM3+VISTA+TAM来克服免疫抗性肿瘤。
