Peptide drugs: a new direction in cancer immunotherapy

Cancer immunotherapy has emerged as a promising approach in cancer treatment and is considered a major advancement after surgical interventions, radiotherapy, chemotherapy, and targeted therapy. The clinical use of immunotherapeutic drugs, particularly antibody-based drugs that target immune checkpoints, has notably increased~1.

Design of a novel chimeric peptide via dual blockade of CD47/SIRPαand PD-1/PD-L1 for cancer immunotherapy

Although immune checkpoint inhibition has been shown to effectively activate antitumor immunity in various tumor types,only a small subset of patients can benefit from PD-1/PD-L1 blockade.CD47 expressed on tumor cells protects them from phagocytosis through interaction with SIRPαon macrophages,while PD-L1 dampens T cell-mediated tumor killing.Therefore,dual targeting PD-L1 and CD47 may improve the efficacy of cancer immunotherapy.A chimeric peptide Pal-DMPOP was designed by conjugating the double mutation of CD47/SIRPαblocking peptide(DMP)with the truncation of PD-1/PD-L1 blocking peptide OPBP-1(8-12)and was modified by a palmitic acid tail.Pal-DMPOP can significantly enhance macrophage-mediated phagocytosis of tumor cells and activate primary T cells to secret IFN-γin vitro.Due to its superior hydrolysis-resistant activity as well as tumor tissue and lymph node targeting properties,Pal-DMPOP elicited stronger anti-tumor potency than Pal-DMP or OPBP-1(8-12)in immune-competent MC38 tumor-bearing mice.The in vivo anti-tumor activity was further validated in the colorectal CT26 tumor model.Furthermore,Pal-DMPOP mobilized macrophage and T-cell anti-tumor responses with minimal toxicity.Overall,the first bispecific CD47/SIRPαand PD-1/PD-L1 dual-blockade chimeric peptide was designed and exhibited synergistic anti-tumor efficacy via CD8^(+)T cell activation and macrophage-mediated immune response.The strategy could pave the way for designing effective therapeutic agents for cancer immunotherapy.

A novel cyclic peptide targeting LAG-3 for cancer immunotherapy by activating antigenspecific CD8^+ T cell responses

PD-1 and CTLA-4 antibodies offer great hope for cancer immunotherapy.However,many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient immune activation.The combination of checkpoint blockers has been proposed to increase the response rates.Besides,antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration problems.In this study,we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting LAG-3.As a result,C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR(MHC-II).Additionally,C25 could significantly stimulate CD8^+T cell activation in human PBMCs.The results also demonstrated that C25 could inhibit tumor growth of CT26,B16 and B 16-OVA bearing mice,and the infiltration of CD8^+T cells was significantly increased while FOXP3^+Tregs significantly decreased in the tumor site.Furthermore,the secretion of IFN-γby CD8^+T cells in spleen,draining lymph nodes and especially in the tumors was promoted.Simultaneously,we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide,and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects via CD8+T cells but not direct killing.In conclusion,cyclic peptide C25 provides a rationale for targeting the immune checkpoint,by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity,and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.

Tryptophan 2,3-dioxygenase 2 controls M2 macrophages polarization to promote esophageal squamous cell carcinoma progression via AKT/GSK3β/IL-8 signaling pathway

Tryptophan 2,3-dioxygnease 2(TDO2) is specific for metabolizing tryptophan to kynurenine(KYN),which plays a critical role in mediating immune escape of cancer.Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers,its tumor-promoting role in esophageal squamous cell carcinoma(ESCC) remains unclear.Here,we observed that TDO2 was overexpressed in ESCC tis sues and correlated significantly with lymph node metastasis,advanced clinical stage,and unfavorable prognosis.Functional experiments showed that TDO2 promoted tumor cell proliferation,migration,and colony formation,which could be prevented by inhibition of TDO2 and aryl hydrocarb on receptor(AHR).Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model,tumor burden of C57 BL/6 mice with ESCC induced by 4-NQO,enhance the expression of phosphorylated AKT,with subsequent pho sphorylation of GSK3β,and polarization of M2 macrophages by upregulating interleukin-8(IL-8) to accelerate tumor progression in the tumor microenvironment(TME).Collectively,our results discovered that TDO2 could upregulate IL-8 through AKT/GSK3β to direct the polarization of M2 macrophages in ESCC,and suggested that TDO2 could represent as an attractive therapeutic target and prognostic marker to ESCC.