Pan-cancer analysis reveals that neurotrophin signaling correlates positively with anti-tumor immunity, clinical outcomes, and response to targeted therapies and immunotherapies in cancer
Section snippets
Background
Recently, immunotherapy has achieved success in treating various cancers [1], [2]. Particularly, immune checkpoint inhibitors (ICIs) targeting PD-1 (programmed cell death protein 1) and its ligand PD-L1 (programmed cell death 1 ligand) have been used for treating diverse cancers [1]. However, only a subset of cancer patients is responsive to ICIs [3]. To improve the effect of ICIs, certain molecular determinants of response to ICIs have been identified, including tumor mutation burden (TMB) [4]
Datasets
We downloaded RNA-Seq gene expression profiles (RSEM normalized), somatic mutations, somatic CNAs, and clinical data for 33 TCGA cancer types from the genomic data commons data portal (https://portal.gdc.cancer.gov/). The 33 cancer types included adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous-cell carcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid neoplasm diffuse large B-cell lymphoma
Association between NS and immune signatures in cancer
Strikingly, in 27 of the 33 cancer types, NS scores had a significant positive correlation with CD8+ T cell scores (Spearman correlation, P < 0.05) (Fig. 1A). Interestingly, the five cancer types in which NS scores showed the strongest positive correlations with CD8+ T cell scores were all digestive cancers, including PAAD (ρ = 0.68), CHOL (ρ = 0.64), COAD (ρ = 0.59), STAD (ρ = 0.55), and READ (ρ = 0.52). Only in THYM, NS scores had a significant negative correlation with CD8+ T cell scores (P
Discussion
For the first time, we analyzed associations of NS with anti-tumor immune signatures, tumor immunity-related molecular and genomic features, and clinical features in a wide variety of cancers (Supplementary Table S4). We revealed a significant positive association between NS and anti-tumor immune response in diverse cancers. In particular, in several digestive cancers, including pancreatic, gastric, colorectal, and bile duct cancers, NS and anti-tumor immune signatures showed the strongest
Conclusions
Our findings suggest that NS is a positive biomarker for anti-tumor immunity, response to immunotherapies and targeted therapies, and favorable clinical outcomes in diverse cancers.
The following are the supplementary data related to this article.
Ethics approval and consent to participate
Ethical approval was waived since we used only publicly available data and materials in this study.
Consent for publication
Not applicable.
Availability of data and material
All data associated with this study are available within the paper and its supplementary data files.
Funding
This work was supported by the China Pharmaceutical University (grant number 3150120001 to XW).
CRediT authorship contribution statement
QF performed data analyses and helped prepare for the manuscript. DS performed data analyses and helped prepare for the manuscript. XW conceived of the research, designed the methods, and wrote the manuscript. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no competing interests.
Acknowledgments
Not applicable.
References (51)
Increased glycolysis correlates with elevated immune activity in tumor immune microenvironment
EBioMedicine
(2019)TP53 mutations promote immunogenic activity in breast cancer
J. Oncol.
(2019)Correlate the TP53 mutation and the HRAS mutation with immune signatures in head and neck squamous cell cancer
Comput. Struct. Biotechnol. J.
(2019)The neuronal influence on tumor progression
Biochim. Biophys. Acta
(2011)- et al.
Trk receptors: mediators of neurotrophin action
Curr. Opin. Neurobiol.
(2001) Targeting neurotrophin signaling in cancer: the renaissance
Pharmacol. Res.
(2018)Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma
Cell
(2016)Molecular and genetic properties of tumors associated with local immune cytolytic activity
Cell
(2015)Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade
Cell Rep.
(2017)- et al.
Cancer immunotherapy using checkpoint blockade
Science
(2018)
CAR T cell immunotherapy for human cancer
Science
Immune checkpoint inhibitors: recent progress and potential biomarkers
Exp. Mol. Med.
Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers
Mol. Cancer Ther.
The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy
Cancer Discov.
PD-L1 expression as a predictive biomarker in cancer immunotherapy
Mol. Cancer Ther.
Combination immunotherapy: a road map
J. Immunother. Cancer
Combination of DC/CIK adoptive T cell immunotherapy with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients: a prospective patients’ preference-based study (PPPS)
Clin. Transl. Oncol.
Current clinical trials testing the combination of immunotherapy with radiotherapy
J. Immunother. Cancer
Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC)
Ther. Adv. Med. Oncol.
CDK4/6 inhibition triggers anti-tumour immunity
Nature
ARID1A mutations correlate with increased immune activity in gastrointestinal cancer
Cells
ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade
Nat. Med.
KALRN mutations promote antitumor immunity and immunotherapy response in cancer
J. Immunother. Cancer
Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma
Clin. Cancer Res.
Role of tumor microenvironment in tumorigenesis
J. Cancer
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