Immune checkpoint expression on peripheral cytotoxic lymphocytes in cervical cancer patients: moving beyond the PD‐1/PD‐L1 axis,Clinical & Experimental Immunology

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Immune checkpoint expression on peripheral cytotoxic lymphocytes in cervical cancer patients: moving beyond the PD‐1/PD‐L1 axis
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2020-12-11 , DOI: 10.1111/cei.13561
F Solorzano-Ibarra ₁ , A G Alejandre-Gonzalez ₁ , P C Ortiz-Lazareno ₂ , B E Bastidas-Ramirez ₁ , A Zepeda-Moreno ₃ , M C Tellez-Bañuelos ₄ , N Banu ₁ , O J Carrillo-Garibaldi ₅ , A Chavira-Alvarado ₆ , M R Bueno-Topete ₁ , S Del Toro-Arreola _{1,

7} , J Haramati ₄

Affiliation

Immune checkpoint therapy to reverse natural killer (NK) and T cell exhaustion has emerged as a promising treatment in various cancers. While anti‐programmed cell death 1 (PD‐1) pembrolizumab has recently gained Food and Drug Administration (FDA) approval for use in recurrent or metastatic cervical cancer, other checkpoint molecules, such as T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine‐based inhibition motif (ITIM) domains (TIGIT) and T cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3), have yet to be fully explored in this disease. We report expression of TIGIT, Tim‐3 and PD‐1 on subsets of peripheral blood NK (CD56^dim/negCD16^{bright/dim/neg} and CD56^brightCD16^dim/neg) and T cells. The percentages of these cells were increased in women with cervical cancer and pre‐malignant lesions. PD‐1⁺ NK and T cells were likely to co‐express TIGIT and/or Tim‐3. These cells, with an apparently ‘exhausted’ phenotype, were augmented in patients. A subset of cells were also natural killer group 2 member D (NKG2D)‐ and DNAX accessory molecule 1 (DNAM‐1)‐positive. PD‐1^int and PD‐1^high T cells were notably increased in cervical cancer. Soluble programmed cell death ligand 1 (PD‐L1) was higher in cancer patient blood versus healthy donors and we observed a positive correlation between sPD‐L1 and PD‐1⁺ T cells in women with low‐grade lesions. Within the cancer group, there were no significant correlations between sPD‐L1 levels and cervical cancer stage. However, when comparing cancer versus healthy donors, we observed an inverse association between sPD‐L1 and total T cells and a correlation between sPD‐L1 and CD56^dim NK cells. Our results may show an overview of the immune response towards pre‐cancerous lesions and cervical cancer, perhaps giving an early clue as to whom to administer blocking therapies. The increase of multiple checkpoint markers may aid in identifying patients uniquely responsive to combined antibody therapies.

中文翻译：

宫颈癌患者外周细胞毒性淋巴细胞免疫检查点表达：超越PD-1/PD-L1轴

逆转自然杀伤 (NK) 和 T 细胞耗竭的免疫检查点疗法已成为治疗各种癌症的有希望的疗法。虽然抗程序性细胞死亡 1 (PD-1) 派姆单抗最近已获得美国食品和药物管理局 (FDA) 批准用于复发性或转移性宫颈癌，但其他检查点分子，如带有免疫球蛋白 (Ig) 的 T 细胞免疫受体和免疫受体酪氨酸基于抑制基序 (ITIM) 结构域 (TIGIT) 和 T 细胞免疫球蛋白和粘蛋白结构域 - 3 (Tim-3) 尚未在该疾病中得到充分探索。我们报告了 TIGIT、Tim-3 和 PD-1 在外周血 NK 亚群上的表达（CD56 ^dim/neg CD16 ^{bright/dim/neg}和 CD56 ^bright CD16 ^dim/neg) 和 T 细胞。这些细胞的百分比在患有宫颈癌和癌前病变的女性中增加。PD-1 ⁺ NK 和 T 细胞可能共同表达 TIGIT 和/或 Tim-3。这些具有明显“疲惫”表型的细胞在患者体内增加。一部分细胞也呈自然杀伤组 2 成员 D (NKG2D) 和 DNAX 辅助分子 1 (DNAM-1) 阳性。PD-1 ^int和 PD-1^高T 细胞在宫颈癌中显着增加。与健康供体相比，癌症患者血液中的可溶性程序性细胞死亡配体 1 (PD-L1) 更高，我们观察到 sPD-L1 和 PD-1 ^{+之间呈正相关}低级别病变女性的 T 细胞。在癌症组中，sPD-L1水平与宫颈癌分期之间没有显着相关性。然而，在比较癌症与健康供体时，我们观察到 sPD-L1 与总 T 细胞之间存在负相关，以及 sPD-L1 与 CD56 ^dim NK 细胞之间存在相关性。我们的结果可能会显示对癌前病变和宫颈癌的免疫反应的概述，也许可以提供有关谁进行阻断疗法的早期线索。多个检查点标记的增加可能有助于识别对联合抗体疗法有独特反应的患者。

更新日期：2020-12-11

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