Volpin Valentina, Michels Tillmann, Sorrentino Antonio, Menevse Ayse N, Knoll Gertrud, Ditz Madlen, Milenkovic Vladimir M, Chen Chih-Yeh, Rathinasamy Anchana, Griewank Klaus, Boutros Michael, Haferkamp Sebastian, Berneburg Mark, Wetzel Christian H, Seckinger Anja, Hose Dirk, Goldschmidt Hartmut, Ehrenschwender Martin, Witzens-Harig Mathias, Szoor Arpad, Vereb Gyorgy, Khandelwal Nisit, Beckhove Philipp
Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
German Cancer Research Center (DKFZ), Translational Immunology, Heidelberg, Germany.
Cancer Immunol Res. 2020 Sep;8(9):1163-1179. doi: 10.1158/2326-6066.CIR-19-0608. Epub 2020 Jul 14.
The success of cancer immunotherapy is limited by resistance to immune checkpoint blockade. We therefore conducted a genetic screen to identify genes that mediated resistance against CTLs in anti-PD-L1 treatment-refractory human tumors. Using PD-L1-positive multiple myeloma cells cocultured with tumor-reactive bone marrow-infiltrating CTL as a model, we identified calcium/calmodulin-dependent protein kinase 1D (CAMK1D) as a key modulator of tumor-intrinsic immune resistance. CAMK1D was coexpressed with PD-L1 in anti-PD-L1/PD-1 treatment-refractory cancer types and correlated with poor prognosis in these tumors. CAMK1D was activated by CTL through Fas-receptor stimulation, which led to CAMK1D binding to and phosphorylating caspase-3, -6, and -7, inhibiting their activation and function. Consistently, CAMK1D mediated immune resistance of murine colorectal cancer cells The pharmacologic inhibition of CAMK1D, on the other hand, restored the sensitivity toward Fas-ligand treatment in multiple myeloma and uveal melanoma cells Thus, rapid inhibition of the terminal apoptotic cascade by CAMK1D expressed in anti-PD-L1-refractory tumors via T-cell recognition may have contributed to tumor immune resistance.
癌症免疫疗法的成功受到免疫检查点阻断耐药性的限制。因此，我们进行了一项基因筛选，以确定在抗PD-L1治疗难治性人类肿瘤中介导对细胞毒性T淋巴细胞（CTL）耐药的基因。以与肿瘤反应性骨髓浸润性CTL共培养的PD-L1阳性多发性骨髓瘤细胞为模型，我们确定钙/钙调蛋白依赖性蛋白激酶1D（CAMK1D）是肿瘤内在免疫耐药性的关键调节因子。在抗PD-L1/PD-1治疗难治性癌症类型中，CAMK1D与PD-L1共表达，并且与这些肿瘤的不良预后相关。CTL通过Fas受体刺激激活CAMK1D，这导致CAMK1D与半胱天冬酶-3、-6和-7结合并使其磷酸化，抑制它们的激活和功能。同样，CAMK1D介导小鼠结肠癌细胞的免疫耐药性。另一方面，对CAMK1D的药理抑制恢复了多发性骨髓瘤和葡萄膜黑色素瘤细胞对Fas配体治疗的敏感性。因此，在抗PD-L1难治性肿瘤中通过T细胞识别表达的CAMK1D对终末凋亡级联反应的快速抑制可能导致了肿瘤免疫耐药性。
