Journal for immunotherapy of cancer · 2022
Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Tingting, Liu Hengqi, Jiao Lei, Zhang Zhenzhen, He Jin, Li Lanfang, Qiu Lihua, Qian Zhengzi, Zhou Shiyong, Gong Wenchen, Meng Bin, Ren Xiubao, Zhang Huilai, Wang Xianhuo
Аннотация
BACKGROUND: Targeting the PD-1/PD-L1/L2 (programmed cell death protein 1/programmed cell death ligand 1/ligand 2) pathway combined with other immunosuppressive signalings, such as CD73/A2aR (A2a adenosine receptor) adenosine signaling, has emerged as a promising strategy for cancer treatment. The genetic characteristics of these immune checkpoints need to be further investigated in diffuse large B-cell lymphoma (DLBCL).
METHODS: We performed whole-exome sequencing/targeted deep sequencing to investigate the genetic characteristics of PD-1/PD-L1/L2 and CD73/A2aR. The immunosuppressive effect of these two pathways on the tumor microenvironment was evaluated via RNA sequencing. Single-cell RNA sequencing was further applied to investigate the dysfunctional CD8+ T cells. In addition, multiplex immunofluorescence staining was used to quantitatively assess the expression of dysfunctional CD8+ T cells in DLBCL.
RESULTS: SP140 was identified as a novel translocation partner for PD-L1, and a new inversion was detected between PD-L1 and PD-L2, both leading to the upregulation of PD-L1 expression. CD73 genetic mutations did not increase mRNA and protein expression. Patients with genetically altered CD73 tended to have a better overall survival than patients with wild-type CD73. Both PD-1/PD-L1 and CD73/A2aR signaling mediated the immunosuppressive microenvironment in DLBCL. The numbers of CD8+ T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8+ T cells (R2=0.974, p=0.013). According to the grades of dysfunctional CD8+ T cells we defined, grade 1 dysfunctional CD8+ T cells, with either PD-1+ or A2aR+, were significantly associated with poorer survival than grade 0 dysfunctional CD8+ T cells, with both PD-1- and A2aR-; and patients with grade 2 dysfunctional CD8+ T cells showed the worst clinical outcomes.
CONCLUSIONS: This study describes the additional genetic basis of PD-L1 overexpression and characterizes certain genetic alterations of CD73/A2aR in DLBCL. The degree of T-cell dysfunction is correlated with clinical outcomes. Strategies that reverse T-cell dysfunction by inhibiting PD-1/PD-L1/L2, particularly in combination with CD73/A2aR, may show potential as effective therapeutic options for DLBCL.
METHODS: We performed whole-exome sequencing/targeted deep sequencing to investigate the genetic characteristics of PD-1/PD-L1/L2 and CD73/A2aR. The immunosuppressive effect of these two pathways on the tumor microenvironment was evaluated via RNA sequencing. Single-cell RNA sequencing was further applied to investigate the dysfunctional CD8+ T cells. In addition, multiplex immunofluorescence staining was used to quantitatively assess the expression of dysfunctional CD8+ T cells in DLBCL.
RESULTS: SP140 was identified as a novel translocation partner for PD-L1, and a new inversion was detected between PD-L1 and PD-L2, both leading to the upregulation of PD-L1 expression. CD73 genetic mutations did not increase mRNA and protein expression. Patients with genetically altered CD73 tended to have a better overall survival than patients with wild-type CD73. Both PD-1/PD-L1 and CD73/A2aR signaling mediated the immunosuppressive microenvironment in DLBCL. The numbers of CD8+ T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8+ T cells (R2=0.974, p=0.013). According to the grades of dysfunctional CD8+ T cells we defined, grade 1 dysfunctional CD8+ T cells, with either PD-1+ or A2aR+, were significantly associated with poorer survival than grade 0 dysfunctional CD8+ T cells, with both PD-1- and A2aR-; and patients with grade 2 dysfunctional CD8+ T cells showed the worst clinical outcomes.
CONCLUSIONS: This study describes the additional genetic basis of PD-L1 overexpression and characterizes certain genetic alterations of CD73/A2aR in DLBCL. The degree of T-cell dysfunction is correlated with clinical outcomes. Strategies that reverse T-cell dysfunction by inhibiting PD-1/PD-L1/L2, particularly in combination with CD73/A2aR, may show potential as effective therapeutic options for DLBCL.