Investigating Cell-Cell Crosstalk in Pre- and Post- Programmed Cell Death-1 (PD-1) Targeted Therapy Tumours Using Single-Cell RNA-Sequencing Analysis

Background: Currently, a significant proportion of cancer patients cannot benefit from programmed cell death-1 (PD-1) targeted therapy. An intractable problem exists regarding how to overcome the drug resistance. Methods: Single-cell RNA sequence data of 53030 cells from paired before and after anti-PD1 therapy tumors were analyzed. To investigate the specific mechanisms of response or resistance to anti-PD1 therapy, cell-cell interaction analyses were performed to investigate the differences between pre-treat responders and non-responders and relative differences of changes from pre- to post- treatment status between responders and non-responders. Similar bulk-sequence data were used to validate our results. Further, we prioritized genes with potential for developing combination anti-PD1 therapy using “TIDE” platform. Findings: We identified several pre-existing different cell-cell interactions based on pre-treatment data of responders and non-responders, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Further, relative differences of changes from pre- to post- treatment between responders and non-responders were assessed. On the whole, cell-cell interactions in CD4+T cells/CD8+ acting T cells/myofibroblasts/NK cells/plasma cells/proliferative T cells to other cells were relatively up-regulated in responders versus non-responders, while those in B cells/CAFs/endothelial cells/macrophages to other cells were relatively down-regulated. Specifically, relative differences of changes from pre- to post- treatment between responders and non-responders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. Finally, AXL, AREG, CXCL12, WNT5A were preserved after prioritization by “TIDE”. Interpretation: These results uncovered the mechanisms of anti-PD1 therapy and offered abundant clues to potential strategies regarding combination therapy with anti-PD1 to improve the efficacy. Funding: Not applicable. Declaration of Interests: The authors have no conflicts of interest to declare.