PMID- 33868792 OWN - NLM STAT- MEDLINE DCOM- 20210802 LR - 20210802 IS - 2162-402X (Electronic) IS - 2162-4011 (Print) IS - 2162-4011 (Linking) VI - 10 IP - 1 DP - 2021 Apr 2 TI - Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data. PG - 1908010 LID - 10.1080/2162402X.2021.1908010 [doi] LID - 1908010 AB - Currently, a significant proportion of cancer patients do not benefit from programmed cell death-1 (PD-1)-targeted therapy. Overcoming drug resistance remains a challenge. In this study, single-cell RNA sequencing and bulk RNA sequencing data from samples collected before and after anti-PD-1 therapy were analyzed. Cell-cell interaction analyses were performed to determine the differences between pretreatment responders and nonresponders and the relative differences in changes from pretreatment to posttreatment status between responders and nonresponders to ultimately investigate the specific mechanisms underlying response and resistance to anti-PD-1 therapy. Bulk-RNA sequencing data were used to validate our results. Furthermore, we analyzed the evolutionary trajectory of ligands/receptors in specific cell types in responders and nonresponders. Based on pretreatment data from responders and nonresponders, we identified several different cell-cell interactions, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Furthermore, relative differences in the changes from pretreatment to posttreatment status between responders and nonresponders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. In trajectory analyses of tumor-specific exhausted CD8 T cells using ligand/receptor genes, we identified a cluster of T cells that presented a distinct pattern of ligand/receptor expression. They highly expressed suppressive genes like HAVCR2 and KLRC1, cytotoxic genes like GZMB and FASLG and the tissue-residence-related gene CCL5. These cells had increased expression of survival-related and tissue-residence-related genes, like heat shock protein genes and the interleukin-7 receptor (IL-7R), CACYBP and IFITM3 genes, after anti-PD-1 therapy. These results reveal the mechanisms underlying anti-PD-1 therapy response and offer abundant clues for potential strategies to improve immunotherapy. CI - (c) 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. FAU - Jiang, Yi-Quan AU - Jiang YQ AUID- ORCID: 0000-0002-9003-943X AD - Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou China. FAU - Wang, Zi-Xian AU - Wang ZX AD - Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Artificial Intelligence Laboratory of Sun Yat-Sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. FAU - Zhong, Ming AU - Zhong M AD - Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Artificial Intelligence Laboratory of Sun Yat-Sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. FAU - Shen, Lu-Jun AU - Shen LJ AD - Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou China. FAU - Han, Xue AU - Han X AD - Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou China. FAU - Zou, Xuxiazi AU - Zou X AD - Department of Breast Surgery, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Artificial Intelligence Laboratory of Sun Yat-Sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. FAU - Liu, Xin-Yi AU - Liu XY AD - MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. FAU - Deng, Yi-Nan AU - Deng YN AD - Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-sen University, Guangzhou, China. FAU - Yang, Yang AU - Yang Y AD - Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-sen University, Guangzhou, China. FAU - Chen, Gui-Hua AU - Chen GH AD - Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-sen University, Guangzhou, China. FAU - Deng, Wuguo AU - Deng W AD - Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Artificial Intelligence Laboratory of Sun Yat-Sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. FAU - Huang, Jin-Hua AU - Huang JH AD - Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210402 PL - United States TA - Oncoimmunology JT - Oncoimmunology JID - 101570526 RN - 0 (CACYBP protein, human) RN - 0 (Calcium-Binding Proteins) RN - 0 (IFITM3 protein, human) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Membrane Proteins) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (RNA-Binding Proteins) RN - 63231-63-0 (RNA) SB - IM MH - Apoptosis MH - Calcium-Binding Proteins MH - Cell Communication MH - Humans MH - Immune Checkpoint Inhibitors MH - Membrane Proteins MH - *Neoplasms/drug therapy MH - *Programmed Cell Death 1 Receptor/genetics MH - RNA MH - RNA-Binding Proteins MH - Sequence Analysis, RNA PMC - PMC8023241 OTO - NOTNLM OT - Single-cell rna sequencing OT - cell-cell interaction OT - immune checkpoint blockade OT - immunotherapy OT - programmed cell death-1 COIS- No potential competing interest was reported by the authors. EDAT- 2021/04/20 06:00 MHDA- 2021/08/03 06:00 PMCR- 2021/04/02 CRDT- 2021/04/19 06:29 PHST- 2021/04/19 06:29 [entrez] PHST- 2021/04/20 06:00 [pubmed] PHST- 2021/08/03 06:00 [medline] PHST- 2021/04/02 00:00 [pmc-release] AID - 1908010 [pii] AID - 10.1080/2162402X.2021.1908010 [doi] PST - epublish SO - Oncoimmunology. 2021 Apr 2;10(1):1908010. doi: 10.1080/2162402X.2021.1908010.