增殖扩散TCF1+ CD8+ T cells 的可能路径（一）

ICB等T细胞相关免疫治疗遇到的主要难题之一是T Cell Exhaustion T细胞耗竭。

《Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy》

“Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.”

. m- e& a) p* t" RICB免疫治疗与其要靠逆转T细胞耗竭，不如增殖扩散TCF1+ CD8 T细胞。

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* k+ f5 a0 l" C! x5 }现搜集整理增殖扩散TCF1+ CD8 T细胞的部分途径如下：
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一、表观遗传机制
1、抑制ezh2
《Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy》

“Tazemetestat induced T cell epigenetic reprogramming and increased the expression of the self-renewing T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells.”

: Y6 ?' _: t0 v$ pEZH2的靶向药有tazemetostat他泽司他，替代药物有利巴韦林。

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2、抑制lsd1

《LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade》
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“Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8+ T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8+ T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. ”
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+ q# X2 m, ?2 J# H& ZLSD1的替代药物有Tranylcypromine。

' h' A& a" n% c# Y) }( J3、抑制hdac
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) m/ l$ Y' b1 f# M4 x2 t《Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity》
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! X1 [" l0 s) K2 q. P5 d/ X“Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1.”
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HDAC的靶向药有西达本胺等药物，替代药物有丙戊酸、氟桂利嗪。

二、抑制AXL

# z  G. Q% k3 y《AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells》

“Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors.”

AXL抑制剂的靶向药有Merestinib梅沙替尼，替代药物有昂丹司琼、吗丁啉。

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# N+ g; d! ^  |; F& Z三、静脉注射连接新抗原肽和Toll样受体7/8激动剂(SNP-7/8a)的纳米颗粒疫苗

3 w5 L  v8 o& Y5 k6 v0 K% D/ N$ P《Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells》

. p! \3 m) y% E* p- l“Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). ”


四、抑制nrp1
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《Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity》
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“Here we report that mice with a CD8+ T cell-restricted neuropilin-1 (NRP1) deletion exhibited substantially enhanced protection from tumor rechallenge and sensitivity to anti-PD1 immunotherapy, despite unchanged primary tumor growth. ”
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) Y& _9 X/ R  b3 t# F- jNrp1抑制剂的替代药物有普萘洛尔、艾曲波帕、格列美脲、西格列汀、度他雄胺、溴隐亭。