Peptides that immunoactivate the tumor microenvironment

Abstract

Cancer immunotherapy has achieved positive clinical outcomes and is revolutionizing cancer treatment. However, cancer immunotherapy has thus far failed to improve outcomes for most "cold tumors", which are characterized by low infiltration of immune cells and immunosuppressive tumor microenvironment. Enhancing the responsiveness of cold tumors to cancer immunotherapy by stimulating the components of the tumor microenvironment is a strategy pursued in the last decade. Currently, most of the agents used to modify the tumor microenvironment are small molecules or antibodies. Small molecules exhibit low affinity and specificity towards the target and antibodies have shortcomings such as poor tissue penetration and high production cost. Peptides may overcome these drawbacks and therefore are promising materials for immunomodulating agents. Here we systematically summarize the currently developed immunoactivating peptides and discuss the potential of peptide therapeutics in cancer immunology.

Keywords: Immuno-oncology; Immunomodulation; Immunotherapy; Therapeutic peptides; Tumor microenvironment.

Fig. 1.

Peptides targeting the tumor microenvironment.

Fig. 2.

Peptides targeting immune checkpoint molecules. The majority of the peptides are inhibitors for the PD-1/PD-L1 pathway. Recently, peptides inhibiting newly identified immune checkpoints LAG-3 and TIGIT have been developed. Further development of peptides targeting immune checkpoints other than PD-1/PD-L1 is expected to improve the response rate of immune checkpoint inhibitors.

Fig. 3.

Peptides targeting Tregs. FOXP3 is a biomarker of Tregs which forms a complex with numerous transcription factors and chromatin modifying factors to regulate the expression of genes related to Treg differentiation and the maintenance of its immunosuppressive phenotype. Peptides targeting FOXP3 activate transcription factors such as NFAT1 and RUNX1 by releasing them from the inhibition by FOXP3. The activation of these transcription factors leads to the suppression of Treg activity. NRP-1 and CXCR4 are other targets highly expressed in intratumoral Tregs. TGF-β is a major immunosuppressive cytokine secreted by Tregs, and therefore inhibitors for TGF-β suppress the function of Tregs. Inhibition of tumor intrinsic β-catenin suppresses the secretion of Treg recruiting chemokines, which consequently reduce the infiltration of Tregs in the tumor.

Fig. 4.

Peptides targeting TAMs. Several peptides binding CD206, which is a prominent biomarker of M2-like macrophages, have been developed. IL-4R is also highly expressed on M2-like macrophages. M2pepKLA is another peptide binding M2-like macrophages although the binding target is unknown. Peptide R is a CXCR4 inhibitory peptide which promotes the M1 feature of TAMs.