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》
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“Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.”
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ICB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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7 L) ]4 x. y8 o  d0 C. }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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. E+ _, L3 V, d7 l8 E* g一、表观遗传机制
. r; |; M/ b& ]/ R' k% @; V1 ~1、抑制ezh2
9 H) N6 z/ F/ S( `《Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy》
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“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.”

EZH2的靶向药有tazemetostat他泽司他，替代药物有利巴韦林。


" X+ \8 F& M1 I2、抑制lsd1
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' n& U, ]) g4 M《LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade》

( w2 h9 F0 S2 o, }“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. ”

5 n  l4 @1 @5 S' m" fLSD1的替代药物有Tranylcypromine。
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) F7 n( |. i% D; I- S1 F3 a3、抑制hdac

《Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity》
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“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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. V2 t, p4 Y( L% _* a/ CHDAC的靶向药有西达本胺等药物，替代药物有丙戊酸、氟桂利嗪。
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( s$ M. C* b. E3 Z2 u6 {$ ?+ Y- B二、抑制AXL

$ v: o/ |. w$ ?" B9 ?, x4 z. c《AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells》
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“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.”
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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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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

《Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells》
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“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). ”
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& g9 U$ ?* B- \& W3 K- Q) x) Z" B四、抑制nrp1
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( y8 K3 P9 x, |* C+ A1 k) Q《Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity》

“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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Nrp1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。