Although immunotherapies have achieved remarkable salutary effects among subgroups of advanced cancers, most patients do not respond. We comprehensively evaluated biomarkers associated with the "cancer-immunity cycle" in the pan-cancer setting in order to understand the immune landscape of metastatic malignancies as well as anti-PD-1/PD-L1 inhibitor resistance mechanisms. Interrogation of 51 markers of the cancer-immunity cycle was performed in 101 patients with diverse malignancies using a clinical-grade RNA sequencing assay. Overall, the immune phenotypes demonstrated overexpression of multiple checkpoints including VISTA (15.8% of 101 patients), PD-L2 (10.9%), TIM3 (9.9%), LAG3 (8.9%), PD-L1 (6.9%) and CTLA4 (3.0%). Additionally, aberrant expression of macrophage-associated markers (e.g. CD68 and CSF1R; 11-23%), metabolic immune escape markers (e.g. ADORA2A and IDO1; 9-16%) and T-cell priming markers (e.g. CD40, GITR, ICOS and OX40; 4-31%) were observed. Most tumors (87.1%, 88/101) expressed distinct immune portfolios, with a median of six theoretically actionable biomarkers (pharmacologically tractable by Food and Drug Administration approved agents [on- or off-label] or with agents in clinical development). Overexpression of TIM-3, VISTA and CD68 were significantly associated with shorter progression-free survival (PFS) after anti-PD-1/PD-L1-based therapies (among 39 treated patients) (all P < .01). In conclusion, cancer-immunity cycle biomarker evaluation was feasible in diverse solid tumors. High expression of alternative checkpoints TIM-3 and VISTA and of the macrophage-associated markers CD68 were associated with significantly worse PFS after anti-PD-1/PD-L1-based therapies. Most patients had distinct and complex immune expression profiles suggesting the need for customized combinations of immunotherapy.

中文翻译：

---

TIM3/VISTA 检查点和 CD68 巨噬细胞相关标记物的表达与抗 PD1/PDL1 耐药性相关：免疫图异质性的影响。


尽管免疫疗法在晚期癌症亚组中取得了显着的有益效果，但大多数患者没有反应。我们全面评估了泛癌环境中与“癌症-免疫循环”相关的生物标志物，以了解转移性恶性肿瘤的免疫格局以及抗 PD-1/PD-L1 抑制剂耐药机制。使用临床级 RNA 测序分析对 101 名患有不同恶性肿瘤的患者进行了癌症免疫循环的 51 种标记物的询问。总体而言，免疫表型显示多个检查点过度表达，包括 VISTA（101 名患者中的 15.8%）、PD-L2（10.9%）、TIM3（9.9%）、LAG3（8.9%）、PD-L1（6.9%）和 CTLA4（ 3.0%）。此外，巨噬细胞相关标记物（例如CD68和CSF1R；11-23%）、代谢免疫逃逸标记物（例如ADORA2A和IDO1；9-16%）和T细胞启动标记物（例如CD40、GITR、ICOS和观察到 OX40；4-31%)。大多数肿瘤（87.1%，88/101）表达不同的免疫组合，平均有六种理论上可行的生物标志物（药理学上可通过食品和药物管理局批准的药物[标签内或标签外]或临床开发中的药物处理）。 TIM-3、VISTA 和 CD68 的过度表达与基于抗 PD-1/PD-L1 的治疗后较短的无进展生存期 (PFS) 显着相关（在 39 名接受治疗的患者中）（所有 P < .01）。总之，癌症免疫周期生物标志物评估在多种实体瘤中是可行的。替代检查点 TIM-3 和 VISTA 以及巨噬细胞相关标记物 CD68 的高表达与基于抗 PD-1/PD-L1 的治疗后显着较差的 PFS 相关。 大多数患者具有独特且复杂的免疫表达谱，表明需要定制的免疫治疗组合。