Bacteria such as the oral microbiome member Peptostreptococcus anaerobius can exacerbate colorectal cancer (CRC) development. Little is known regarding whether these immunomodulatory bacteria also affect antitumour immune checkpoint blockade therapy. Here we show that administration of P. anaerobius abolished the efficacy of anti-PD1 therapy in mouse models of CRC. P. anaerobius both induced intratumoral myeloid-derived suppressor cells (MDSCs) and stimulated their immunosuppressive activities to impair effective T cell responses. Mechanistically, P. anaerobius administration activated integrin α₂β₁–NF-κB signalling in CRC cells to induce secretion of CXCL1 and recruit CXCR2⁺ MDSCs into tumours. The bacterium also directly activated immunosuppressive activity of intratumoral MDSCs by secreting lytC_22, a protein that bound to the Slamf4 receptor on MDSCs and promoted ARG1 and iNOS expression. Finally, therapeutic targeting of either integrin α₂β₁ or the Slamf4 receptor were revealed as promising strategies to overcome P. anaerobius-mediated resistance to anti-PD1 therapy in CRC.

口腔微生物组成员厌氧消化链球菌等细菌可能会加剧结直肠癌 (CRC) 的发展。关于这些免疫调节细菌是否也会影响抗肿瘤免疫检查点阻断疗法，人们知之甚少。在这里，我们证明，在 CRC 小鼠模型中，给予厌氧丙酸杆菌可以消除抗 PD1 疗法的功效。厌氧假单胞菌既能诱导瘤内骨髓源性抑制细胞 (MDSC)，又能刺激其免疫抑制活性，从而损害有效的 T 细胞反应。从机制上讲，厌氧假单胞菌给药激活 CRC 细胞中的整合素 α ₂ β ₁ –NF-κB 信号传导，诱导 CXCL1 分泌并将 CXCR2 ⁺ MDSC 招募到肿瘤中。该细菌还通过分泌lytC_22直接激活瘤内MDSC的免疫抑制活性，lytC_22是一种与MDSC上的Slamf4受体结合并促进ARG1和iNOS表达的蛋白质。最后，整合素 α ₂ β ₁或 Slamf4 受体的治疗靶向被证明是克服CRC 中厌氧杆菌介导的抗 PD1 治疗耐药性的有前途的策略。