Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma

Cancers

Joaquín Miquel¹  Miguel Torralba¹  Julia Peña-Asensio¹  Eduardo Sanz-de-Villalobos¹  Henar Calvo¹  Juan-Ramón Larrubia¹ 

[1] Translational Hepatology Unit, Guadalajara University Hospital, 19002 Gudalajara, Spain;

关键词: hepatocellular carcinoma;    immunotherapy;    PD-1;    PD-L1;    immune check-point inhibitor;    combination therapy;   

DOI  :  10.3390/cancers13081922

来源: DOAJ

【 摘 要 】

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8⁺ T cells is discussed in this review.

【 授权许可】

Unknown