Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance

被引：24

作者：

Amodio, Vito ^{[1
,2
]}

Lamba, Simona ^{[2
]}

Chila, Rosaria ^{[1
,3
]}

Cattaneo, Chiara M. ^{[3
]}

Mussolin, Benedetta ^{[2
]}

Corti, Giorgio ^{[1
,2
]}

Rospo, Giuseppe ^{[1
,2
,3
]}

Berrino, Enrico ^{[2
,8
]}

Tripodo, Claudio ^{[3
,7
]}

Pisati, Federica ^{[9
]}

Bartolini, Alice ^{[2
]}

Aquilano, Maria Costanza ^{[10
]}

Marsoni, Silvia ^{[3
]}

Mauri, Gianluca ^{[3
,4
]}

Marchio, Caterina ^{[2
]}

Abrignani, Sergio ^{[5
,6
]}

Di Nicolantonio, Federica ^{[1
,2
]}

Germano, Giovanni ^{[1
,2
]}

Bardelli, Alberto ^{[1
,2
,11
,12
]}

机构：

[1] Univ Torino, Dept Oncol, I-10060 Candiolo, TO, Italy

[2] FPO IRCCS, Candiolo Canc Inst, I-10060 Candiolo, TO, Italy

[3] IFOM ETS, AIRC Inst Mol Oncol, I-20139 Milan, Italy

[4] Univ Milan, Dept Oncol & Hematooncol, I-20162 Milan, Italy

[5] Ist Nazl Genet Mol INGM Romeo ed Enrica Invernizz, I-20122 Milan, Italy

[6] Univ Milan, Dept Clin Sci & Community Hlth, I-20122 Milan, Italy

[7] Univ Palermo, Dept Hlth Sci, Tumor Immunol Unit, I-90127 Palermo, Italy

[8] Univ Torino, Dept Med Sci, Turin, Italy

[9] Cogentech SCaRL, Histopathol Unit, I-20139 Milan, Italy

[10] ASST Grande Osped Metropolitano Niguarda, Dept Hematol Oncol & Mol Med, I-20162 Milan, Italy

[11] Univ Torino, Dept Oncol, Turin, Italy

[12] IFOM ETS, AIRC Inst Mol Oncol, Milan, Italy

来源：

CANCER CELL | 2023年 / 41卷 / 01期

基金：

欧洲研究理事会;

关键词：

MICROSATELLITE INSTABILITY; COLORECTAL-CANCER; LYNCH SYNDROME; TEMOZOLOMIDE; MSH6; 6-THIOGUANINE; GLIOBLASTOMAS; BLOCKADE; BENEFIT;

D O I：

10.1016/j.ccell.2022.12.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Patients affected by colorectal cancer (CRC) with DNA mismatch repair deficiency (MMRd), often respond to immune checkpoint blockade therapies, while those with mismatch repair-proficient (MMRp) tumors gener-ally do not. Interestingly, a subset of MMRp CRCs contains variable fractions of MMRd cells, but it is unknown how their presence impacts immune surveillance. We asked whether modulation of the MMRd fraction in MMR heterogeneous tumors acts as an endogenous cancer vaccine by promoting immune surveillance. To test this hypothesis, we use isogenic MMRp (Mlh1+/+) and MMRd (Mlh1-/-) mouse CRC cells. MMRp/ MMRd cells mixed at different ratios are injected in immunocompetent mice and tumor rejection is observed when at least 50% of cells are MMRd. To enrich the MMRd fraction, MMRp/MMRd tumors are treated with 6-thioguanine, which leads to tumor rejection. These results suggest that genetic and pharmacological mod-ulation of the DNA mismatch repair machinery potentiate the immunogenicity of MMR heterogeneous tumors.

引用

页码：196 / +

页数：20

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