CHI3L1 enhances melanoma lung metastasis via regulation of T cell co-stimulators and CTLA-4/B7 axis.
CHI3L1 enhances melanoma lung metastasis via regulation of T cell co-stimulators and CTLA-4/B7 axis.
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DOI：
10.3389/fimmu.2022.1056397
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
ICOS/ICOSL和CD 28/B7-1/B7-2是T细胞共刺激因子，CTLA-4是免疫检查点抑制剂，在肿瘤的发病机制中起关键作用。几丁质酶3-样-1（CHI 3L 1）在许多癌症中被诱导，在这些癌症中它预示着不良预后并有助于肿瘤转移。在这里，我们证明了CHI 3L 1抑制ICOS、ICOSL和CD 28的表达，同时刺激黑色素瘤肺转移中的CTLA-4和B7部分。我们还证明，RIG样解旋酶先天免疫激活增强T细胞共刺激，抑制CTLA-4和抑制肺转移。在用抗CTLA-4和抗CHI 3L 1抗体组合治疗的黑素瘤肺转移中观察到至少累加的抗肿瘤应答。在用靶向CHI 3L 1和CTLA-4的双特异性抗体处理的T细胞和肿瘤细胞的共培养物中观察到协同细胞毒性T细胞诱导的肿瘤细胞死亡和肿瘤抑制因子PTEN的诱导增强。因此，CHI 3L 1通过抑制T细胞共刺激和刺激CTLA-4促进肺转移。用个体抗体同时靶向CHI 3L 1和CTLA-4轴，并且更有力地用双特异性抗体同时靶向CHI 3L 1和CTLA-4轴，代表了用于肺转移的有前景的治疗策略。
ICOS/ICOSL and CD28/B7-1/B7-2 are T cell co-stimulators and CTLA-4 is an immune checkpoint inhibitor that play critical roles in the pathogenesis of neoplasia. Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it portends a poor prognosis and contributes to tumor metastasis. Here we demonstrate that CHI3L1 inhibits the expression of ICOS, ICOSL and CD28 while stimulating CTLA-4 and the B7 moieties in melanoma lung metastasis. We also demonstrate that RIG-like helicase innate immune activation augments T cell co-stimulation, inhibits CTLA-4 and suppresses pulmonary metastasis. At least additive antitumor responses were seen in melanoma lung metastasis treated with anti-CTLA-4 and anti-CHI3L1 antibodies in combination. Synergistic cytotoxic T cell-induced tumor cell death and the heightened induction of the tumor suppressor PTEN were seen in co-cultures of T and tumor cells treated with bispecific antibodies that target both CHI3L1 and CTLA-4. Thus, CHI3L1 contributes to pulmonary metastasis by inhibiting T cell co-stimulation and stimulating CTLA-4. The simultaneous targeting of CHI3L1 and the CTLA-4 axis with individual and, more powerfully with bispecific antibodies, represent promising therapeutic strategies for pulmonary metastasis.
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影响因子：
16.6
作者：
Koyama S;Akbay EA;Li YY;Herter-Sprie GS;Buczkowski KA;Richards WG;Gandhi L;Redig AJ;Rodig SJ;Asahina H;Jones RE;Kulkarni MM;Kuraguchi M;Palakurthi S;Fecci PE;Johnson BE;Janne PA;Engelman JA;Gangadharan SP;Costa DB;Freeman GJ;Bueno R;Hodi FS;Dranoff G;Wong KK;Hammerman PS
通讯作者：
Hammerman PS
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
24.8
作者：
Heidegger, Simon;Wintges, Alexander;Poeck, Hendrik
通讯作者：
Poeck, Hendrik
影响因子：
32.4
作者：
Esensten JH;Helou YA;Chopra G;Weiss A;Bluestone JA
通讯作者：
Bluestone JA
DOI：
10.1084/jem.20081271
发表时间：
2009-05-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lee CG;Hartl D;Lee GR;Koller B;Matsuura H;Da Silva CA;Sohn MH;Cohn L;Homer RJ;Kozhich AA;Humbles A;Kearley J;Coyle A;Chupp G;Reed J;Flavell RA;Elias JA
通讯作者：
Elias JA