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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9 U- u# b+ T7 ]6 f' c$ @《Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy》

: z" X1 W+ Q* q, E+ L“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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! O5 w2 F+ D% {3 u( j( f3 {& M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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  I" I/ ~1 [3 n' C9 }% u一、表观遗传机制
$ S; B7 ^: T  d4 y. B" W6 ^/ ]1、抑制ezh2
5 q( g! l2 i  T$ k* z: k- N0 D《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.”
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EZH2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》
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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. ”

- ^  a1 C" A7 Y5 P7 t- a2 H: _7 fLSD1的替代药物有Tranylcypromine。
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3、抑制hdac

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

5 z( M2 T) r/ E4 i“Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1.”

8 d" e9 {0 f( E. RHDAC的靶向药有西达本胺等药物，替代药物有丙戊酸、氟桂利嗪。

& p& i. |, V7 }9 X' o$ ~二、抑制AXL

0 _( v' [* i* ^& l7 ]《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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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

8 J) _' l3 ^% z& w《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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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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6 [2 i9 n% {2 [“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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3 [% x& C' v8 INrp1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。