一文看懂免疫组库测序的各种评价指标

当机体产生特异性免疫应答时,TCR的多样性会发生变化,某个或某些T细胞克隆会大量扩增,来对抗异己抗原。免疫组库的分析可以反映机体免疫应答的状态,那么如何利用免疫组库来评价机体的免疫状态呢?小编在这里整理了目前文献中采用的免疫组库参数,与大家共飨盛宴。

1. Shannon’s entropy

“香浓“来源于信息熵,衡量了机体中T细胞克隆的多样性。香浓指数越高,代表T细胞克隆的多样性越高。从公式中可以看出,香浓既考虑了T细胞克隆种类的多少,也考虑了每种克隆的均匀度(频率),Pi代表第i个克隆的频率,R代表克隆种类数。

Ref:

[1]Shannon, C. E. The mathematical theory of communication. 1963.MD Comput. 14, 306–317 (1997).

[2]Ruggiero E, Nicolay J P, Fronza R, et al. High-resolution analysis of the human T-cell receptor repertoire[J]. Nature communications, 2015, 6: 8081.

[3]Jia Q, Wu W, Wang Y, et al. Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer[J]. Nature Communications, 2018, 9.

[4]Rosenthal R, Cadieux E L, Salgado R, et al. Neoantigen-directed immune escape in lung cancer evolution[J]. Nature, 2019: 1.

 

2. Simpson Diversity index

辛普森多样性指数描述的是在测得的克隆群中,连续两次抽样,所得到的克隆属于同一种的概率。它反映的是扩增克隆在克隆群中的地位和作用,若克隆群中扩增克隆所占的多,其它非克隆克隆所占的比例则会减少,那么辛普森指数就会较大,说明克隆多样性较低。辛普森指数越大,说明克隆的多样性更低。

Ref:

[1]Simpson, E. H. Measurement of diversity. Nature 163, 688 (1949).

[2]Jia Q, Wu W, Wang Y, et al. Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer[J]. Nature Communications, 2018, 9.

3. Inverse Simpson Diversity 

逆辛普森多样性指数是辛普森指数的倒数,逆辛普森指数越大,代表克隆的多样性越高。

Ref:

[1]Van Heijst J W J, Ceberio I, Lipuma L B, et al. Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation[J]. Nature medicine, 2013, 19(3): 372.

[2]Ruggiero E, Nicolay J P, Fronza R, et al. High-resolution analysis of the human T-cell receptor repertoire[J]. Nature communications, 2015, 6: 8081.

[3]Strauss-Albee D M, Fukuyama J, Liang E C, et al. Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility[J]. Science translational medicine, 2015, 7(297): 297ra115-297ra115.

[4]Lu J, Van Laethem F, Bhattacharya A, et al. Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire[J]. Nature communications, 2019, 10(1): 1019.

4. Gini-Simpson

Gini-Simpson多样性指数表示在克隆群中随机选取两个克隆序列,两者属于不同种类克隆的概率。Gini-Simpson值越高,代表克隆的多样性越高。

Ref:

[1]Keylock C J. Simpson diversity and the Shannon–Wiener index as special cases of a generalized entropy[J]. Oikos, 2005, 109(1): 203-207.

[2]Venturi V, Kedzierska K, Turner S J, et al. Methods for comparing the diversity of samples of the T cell receptor repertoire[J]. Journal of immunological methods, 2007, 321(1-2): 182-195.

5. Clonality:

Clonality指标更关注于对T细胞的扩增的衡量,Clonality值越大,代表了有部分克隆发生了很大频率的扩增。从公式上来看, 分子H’代表了香浓值,分母H’max代表对所有克隆数目取ln值。

Ref:

[1]Tumeh PC, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature.2014;515:568–571. doi: 10.1038/nature13954.

[2] Johnson D B, Frampton G M, Rioth M J, et al. Targeted next generation sequencing identifies markers of response to PD-1 blockade[J]. Cancer immunology research, 2016, 4(11): 959-967.

[3] Reuben A, Gittelman R, Gao J, et al. TCR repertoire intratumor heterogeneity in localized lung adenocarcinomas: an association with predicted neoantigen heterogeneity and postsurgical recurrence[J]. Cancer discovery, 2017, 7(10): 1088-1097.

6. Evenness

Evenness衡量了克隆的均一程度,Evenness值越高,代表各克隆分布比较均匀,Evenness值越低,代表有一些特异性的克隆发生了扩增。公式的计算方法为:克隆频率高于50%的所有克隆数目与克隆群中所有克隆数目的比值。

Ref:

[1]Postow M A, Manuel M, Wong P, et al. Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma[J]. Journal for immunotherapy of cancer, 2015, 3(1): 23.

[2]Hogan S A, Courtier A, Cheng P F, et al. Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma[J]. Cancer immunology research, 2019, 7(1): 77-85.

这里小编将每种方法都选取了几篇有代表性的文献供大家参考,当然实际文献有更多,欢迎讨论~

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