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。

# J/ J3 K+ @4 }9 u《Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy》
* X* h. {; Y1 v. L1 a9 l
“Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.”
; ?# x7 N' J! n9 k! ]
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。


. ]8 S; z! O- D; [2 @$ @" l  m现搜集整理增殖扩散TCF1+ CD8 T细胞的部分途径如下：

0 D% F3 D9 g  Q1 b6 Q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.”

EZH2的靶向药有tazemetostat他泽司他，替代药物有利巴韦林。
, f5 B3 v1 ^' p5 i6 o7 ?1 g" Y9 A$ v
# h5 E4 g. w) }8 m% _, E
3 p# k2 m, r9 W9 e2、抑制lsd1
  f9 o& `4 Y$ @/ p' @
, r9 n+ L  F. ]5 U1 p8 x《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。

' C9 U+ Q+ k: o+ o# z; I3、抑制hdac
. ~& f6 [  P4 i
《Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity》
9 _* P" F* I# s2 |0 z. b5 }' B* D
5 h$ f- F' Y9 G% W  d6 v“Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1.”
2 W/ _4 r, J  W8 ~. e
$ G4 I# L% U, ~  X' KHDAC的靶向药有西达本胺等药物，替代药物有丙戊酸、氟桂利嗪。
9 B- h5 d9 C8 K$ e; {- C
二、抑制AXL
/ n1 O# b( Y0 z) I
# T& X- s( I: G, M* k, I+ d《AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells》
' A2 m3 Z0 a& t* F9 i5 T. M
- F5 M$ y1 v1 V) X“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.”
5 k/ R. Q1 `1 c& E- X5 I
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。

& D6 l  M/ B8 V
' d9 G( e, `3 ]; m' w# F
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》

“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). ”
4 Y$ @, ?* E7 `. [2 c2 x& p# p
3 ~% A; a7 [( C9 k+ R$ ]! y
, b: X) ?1 o( Q7 R: Y% ]四、抑制nrp1
, W9 N  i4 g' t# K8 F6 ?
6 D$ c  T! t. ?6 k! j. P; d《Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity》
3 A( a  [+ d' q( S! e6 M  Z
- J% b! l4 ]- \7 `8 F) z“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. ”
8 J' F/ B, Y6 W9 W& p2 f! ]# r
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。