The aim of this study was to assess the potential use of a selective small molecule MALT1 inhibitor in solid tumor treatment as an immunotherapy targeting regulatory -cells (Tregs). In vitro, MALT1 inhibition suppressed the proteolytic cleavage of the MALT1-substrate HOIL1 and blocked IL-2 secretion in Jurkat cells. It selectively suppressed the proliferation of PBMC-derived Tregs, with no effect on conventional CD4-cells. In vivo, however, no evident anti-tumor effect was achieved by MALT1 inhibition monotherapy or in combination with anti-CTLA4 in the MB49 cancer model. Despite decreased Treg-frequencies in lymph nodes of tumor-bearing animals, intratumoral Treg depletion was not observed. We also showed that MALT1-inhibition caused a reduction of antigen-specific CD8-cells in an adoptive -cell transfer model. Thus, selective targeting of Tregs would be required to improve the immunotherapeutic effect of MALT1-inhibition. Also, various dosing schedules and combination therapy strategies should be carefully designed and evaluated further.

中文翻译：

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MALT1 抑制抑制抗原特异性 T 细胞反应

本研究的目的是评估选择性小分子 MALT1 抑制剂作为针对调节细胞 (Treg) 的免疫疗法在实体瘤治疗中的潜在用途。在体外，MALT1 抑制抑制了 MALT1 底物 HOIL1 的蛋白水解裂解，并阻止 Jurkat 细胞中 IL-2 的分泌。它选择性地抑制 PBMC 衍生的 Tregs 增殖，对传统 CD4 细胞没有影响。然而，在体内，在 MB49 癌症模型中，通过 MALT1 抑制单一疗法或与抗 CTLA4 联合疗法，没有取得明显的抗肿瘤效果。尽管荷瘤动物淋巴结中 Treg 频率降低，但未观察到瘤内 Treg 耗竭。我们还表明，在过继细胞转移模型中，MALT1 抑制导致抗原特异性 CD8 细胞减少。因此，需要选择性靶向 Tregs 来提高 MALT1 抑制的免疫治疗效果。此外，应仔细设计和进一步评估各种给药方案和联合治疗策略。