Wu, Yang, and Iftikhar et al. showed that CD40 agonist Ab + CpG + anti-PD-L1 therapy improved the efficacy of irreversible electroporation ablation (IRE) in a mouse model of s.c. melanoma with lung metastases. Including CD40 agonism induced greater tumor antigen-specific CD8+ T cell responses, cDC1 maturation, a higher frequency of rare CD8+CD103+ cDC1s, and greater TCM derived-CD103+TCF1+ TRM cell responses than IRE + CpG + anti-PD-L1 or IRE alone. CD103+TCF1+ TRM cells exhibited enhanced mitochondrial content and increased expression of effector cytokines and 41BB-costimulatory-related signaling molecules.
Contributed by Paula Hochman
Background: Melanoma is one of the deadliest forms of skin cancer. Irreversible electroporation (IRE) is an innovative, non-thermal ablation technology for treating irresectable solid cancers. However, most IRE treatments are incapable of cancer eradication and only temporarily prolong patient survival.
Methods: In this study, we developed a novel IRE + Combo treatment regimen that combines IRE-ablation with Combo-adjuvant [CpG, anti-PD-L1 antibody (PD-L1-Ab) and CD40-agonist] and investigated its anti-tumor immunity in a mouse BL6-10OVA (BLOVA) melanoma model.
Results: We demonstrated that inclusion of the CD40-agonist in the IRE + Combo treatment regimen promoted a more robust CD8+ T cell response (6.89%) when compared with IRE + CpG/PD-L1-Ab (2.67%) or IRE alone (0.21%) treatments, leading to eradication of subcutaneous BLOVA melanoma in 5/8 of BLOVA-bearing mice and simultaneous elimination of lung melanoma metastases. Addition of CD40-agonist to the IRE + Combo treatment regimen also induced a higher frequency (17.1%) of CD8+CD103+ conventional type-1 dendritic cells (cDC1s) with up-regulated expression of CD54, CD80, MHC II, Bcl-xL and 41BBL in tumor-drainage lymph nodes (TDLNs) relative to the control IRE + CpG/PD-L1-Ab (12.1%) and IRE alone (9.0%) treatment groups. We also show that CD40-agonist stimulated a higher frequency of CD103+TCF1+ tissue-resident memory T (TRM) cells (32.1%) in TDLNs when compared with the two control (15.3% and 6.7%) treatment groups, and that these TRM cells exhibited enhanced mitochondrial content and greater relative expression of the effector cytokines IFN-γ and TNF-α and the transcriptional regulators TRAF1, p38-MAPK and PGC-1α.
Conclusion: Taken together, this study establishes that the CD40-agonist greatly potentiates the efficacy of IRE-ablation for metastatic melanoma by promoting unexpected CD8+CD103+ cDC1 and CD103+TCF1+ TRM cell responses and suggests the importance of targeting CD40-signaling to improve the efficacy of cancer IRE-ablation therapy.
Author Info: (1) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (2) Saskatoon Cancer Cent
Author Info: (1) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (2) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, China. (3) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (4) Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada. (5) Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada. (6) Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada. (7) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (8) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (9) Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada. (10) Division of Biomedical Engineering, University of Saskatchewan, Saskatoon, SK, Canada. (11) Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, China. jiangjunhong1969@suda.edu.cn. (12) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. jim.xiang@usask.ca. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. jim.xiang@usask.ca.
