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。

8 ~/ R+ i4 E0 \) i: K《Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy》
" \: D2 F' i6 d$ u# |
“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。
: y6 _( o( K+ z+ ?1 z4 `
. {+ c0 f9 Y* L3 D+ n8 ~
现搜集整理增殖扩散TCF1+ CD8 T细胞的部分途径如下：
& C9 M1 f5 ~  f* n
一、表观遗传机制
: ]( h7 X% d, w% Z( w1、抑制ezh2
《Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy》
) C/ y4 j: _, h) x. O! V' `/ d* z+ r
( K$ p$ N+ V" E! g* a“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.”
" Z9 z0 c- j/ {' G" F
EZH2的靶向药有tazemetostat他泽司他，替代药物有利巴韦林。


2、抑制lsd1
7 O8 S1 ?0 P6 D6 h
6 m! {, a7 h* ^3 i# d《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. ”

LSD1的替代药物有Tranylcypromine。
' `# t2 }; ^$ k7 r
' d! b) F$ h" A% l( j0 W, C3、抑制hdac

+ ^( R8 s* a$ J% U7 g0 ~& W《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.”
: l8 i7 ~* L, C/ y1 L
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。
! |  ^4 v2 _3 B
7 v7 ^) C; e" p7 p$ t: t二、抑制AXL

《AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells》
! e0 D. N% _- D: x6 _
) E/ E) G+ x0 S“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.”
' y) W9 S* M, l1 \* n6 R
1 j2 A, y3 [0 c" C8 `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。
4 A2 j  x2 r; x1 |
7 X; a9 {+ y/ m, J& D

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
4 `$ L, h- i. Y8 U0 |
" b$ u2 o9 {8 ]" Z  f7 Q《Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells》
  p6 r! Z( R; D8 N4 }
“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). ”


1 I& O0 U6 v# o' ^. n4 x0 |四、抑制nrp1

《Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity》
0 X8 I1 v$ p' _' [" w/ W" y: F
1 A7 C3 \* X4 X" x$ A' t9 f“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. ”
2 c$ G4 M1 W- o4 |$ T; ?1 `
- _( V- O7 a2 d- J" ENrp1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。