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。
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8 X0 G# y# T$ ~' C1 n《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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. Y8 H) M( ]  U& z1 i“Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.”

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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6 |+ x0 c5 ]6 y# k, i; z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
% y$ b  _; n6 `& C; O《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.”

; K# Q6 w, @8 Q$ G4 }1 X3 fEZH2的靶向药有tazemetostat他泽司他，替代药物有利巴韦林。


2、抑制lsd1
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《LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade》

“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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. k/ }; y; X" CLSD1的替代药物有Tranylcypromine。

3、抑制hdac
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《Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity》

“Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1.”

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

+ d! h0 A& {* F! T  D- O$ U: ]/ e& D《AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells》

2 P# w1 Z7 V0 H, P“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.”

: g/ d$ G/ Z- V, v! h. G3 J$ w; J6 CAXL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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$ S2 I& G7 ^2 z/ k4 `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
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) r4 j7 F, O4 K) I/ S3 u《Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells》
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+ R" l: t+ N6 d2 T“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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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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/ m7 f( G, C2 z; w( R“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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' a! @" l' \' s) Z% G: n0 [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。