放疗与免疫治疗

Primary tumor
1000
800
600
400
200
0
10
12 14 16 18 20
Days after Injection
Second tumor
8C0o0ntrol 8Gy× 3 680G0y× 3 + anti-PD1 anti-PD1
400
200
0
10
12 14 16 18 20
Days after Injection
tumor
Breakthrough of the Year 2013
放射治疗相关免疫效应
诱导肿瘤细胞高表达
• 主要组织相容性复合体1类分子MHC-1 • Fas(CD95)等细胞表面分子
更易被T细胞 识别和杀伤
诱导肿瘤微环境高表达 • 趋化因子和细胞因子
促进T细胞募集 浸润以及促炎性
Formenti S C, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift.[J]. Journal of the National Cancer Institute, 2013, 105(4):256-265.
放疗联合免疫治疗的基础研究
放大助燃作用
Vaccination
Checkpoint GM-CSF ……
Abscopal effect: RT-induced tumor regression in lesions distant from a targeted site
放疗后5天，原发灶内8Gy×3f组 CD4+TILs CD8+TILs较无放疗组明显升高
27
Control 8Gy× 3 8Gy× 3 + anti-PD1 anti-PD1
The Immune Response with Flow cytometry
CD4+T
CD8+T
MDSC
Spleen
20
Spleen
15
Spleen
25
CD11b+ Ly-6C+ (%)
CD3+ CD4+ (%)
➢ Decreased MDSC in spleen and regional lymph nodes prFimirasrtytutummoorr conStreaclaotnedraltutummoorr
pFriimrsatrtyutmumoror coSnetrcaolantdertaulmor
放疗联合anti-PD-1出现明显远隔效应
8Gy×3
MC38(L) (R)
8Gy×3
Baidu NhomakorabeaPD-1mAb×8f
Volume of tumor (mm3) Volume of tumor (mm3)
Day:
0
9 10 11 13
Human PD-1 gene knock-in Mouse & MC38 tumors
CD3+ CD8+ (%)
20 15
10 15
10
10 5
5
5
0
0
0
anti-PD1 anti-PD1
8Gy×3
Control
anti-PD1 anti-PD1
8Gy×3
Control
anti-PD1 anti-PD1
8Gy×3
Control
➢ Combined RT with IT increased both CD4+T & CD8+T
➢ 大分割较常规放疗可激活原发灶和局部淋巴结及脾脏，致免疫反应增强
常大➢规分立分割体割R✓TR放后放T引疗引疗流好流特淋淋于别巴巴常是结结规大内内放T分C细D疗割胞4解本+无T细身释明胞是除显升原变传高化位统疫放S苗疗B作R肿T用瘤对细脾胞脏杀免伤疫外抑，制还可细能胞有的以影下响
✓ 增强或诱发了系列抗肿瘤免疫系统作用 ✓ 肿瘤血管放射损伤而间接杀死肿瘤细胞
+
+
+
8Gy×3
8Gy×3
8Gy×3
✓ In spleen: representing systemic immune response
✓ In Reg-Nodes: representing regional immune
Lymrpehsnopdoe nse
Lymph node
Lymph node
放射治疗相关免疫效应
Formenti S C, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift.[J]. Journal of the National Cancer Institute, 2013, 105(4):256-265.
放疗远位效应并不常见!
DovedcioSncJu, ArrdelnatrdPDA-LL,1Lbiploocwksakdaeb.[hJa].llCaaGn,ceetr aRle. sAecaqruchir,e2d0r1e4s,is7t4a(n1c9e):t5o45fr8a-c5t4io6n8a.ted radiotherapy can be overcome by Lu T, Rmaimcea.[kJr]i.sJhonuarnnaRl,oAfltCiolikniSc,ael tInavle. sTtuigmaotiro-nin,f2il0tr1a1ti,n1g21m(1y0e)lo:4i0d1c5e-l2ls9i.nduce tumor cell resistance to cytotoxic T cells in
放疗与免疫治疗
Paradigm Shift in Cancer Therapy
Historical Paradigm: Targeting Tumor Cells
New Paradigm: Targeting Immune
Lymphocyte
Tumor Cell
Tumor Cell
SCIENCE
放射治疗负性免疫效应
诱导免疫抑制性细胞数量的增加 调节性T淋巴细胞 (regulatory T cells，Tregs) 骨髓来源的抑制性细胞
(Myeloid-derived suppressor cells，MDSCs）
增加肿瘤细胞及微环境中免疫抑制信号的表达 PD-L1 (Programmed death-ligand 1) 转化生长因子B (Transforming growth factor B，TGF-β)