Combined Therapy of PD-1 and KLRG1

Background

Monoclonal antibodies targeting the receptors of immune inhibitory checkpoint have been shown to provide excellent tumor suppression and considerably enhanced patient survival. Programmed death-1 (PD-1) is one of the most famous checkpoint inhibitors. However, a considerable proportion of patients may either not react to therapy or will only see transient advantages. It is critical to study novel receptor targets that may be utilized separately or synergistically with current immunotherapies. Killer cell lectin-like receptor G1 (KLRG1) is an immunological checkpoint receptor expressed primarily on late-differentiated effector CD8⁺ T and NK cells, with a similar affinity to E-cadherin and N-cadherin. Recent research demonstrates that KLRG1 blockade in concert with PD-1 blockade is effective at inhibiting tumor development by enhancing lymphocyte infiltration.

Case 1: Tumor Growth is Depressed by Combined Antibody Treatment

In a metastatic breast cancer mouse model, 4T-1 cells express high-level E-cadherin. Although anti-KLRG1 antibody alone has no influence on primary tumor development, it greatly decreases lung metastases as determined by lung nodule count and lung weight. In another B16F10 melanoma model expressing high levels of N-cadherin, anti-KLRG1 plus anti-PD-1 remarkably suppresses primary tumor development more than each one or control antibody alone. A survival benefit can also be noticed when applying combined therapy. However, the related mechanism has not been uncovered.

Fig.1 Combined treatment of anti-KLRG1 and anti-PD-1 obviously improves the anti-tumor activity.¹

Case 2: The Synergistic Effect of KLRG1 and PD-1 is Based on Effector Cell Infiltration

Another research group illustrates the underlying mechanism of combined immune checkpoint treatment between KLRG1 and PD-1. Similar results are generated in the B16F10 melanoma mouse model, regarding the synergistic effect on reduced tumor volume. Besides, considerable NK cell and CD8⁺ T cell enrichment are noticed in tumors of the mouse with double antibody treatment. Further analysis of NK cells indicates that tumor-infiltrating NK cells display a more mature phenotype (CD27-/CD11b⁺) in the dual blockade-treated cohort. In the tumor microenvironment, the increased frequency and activation of effector CD8⁺ T cells and maturation of NK cells play a critical part in the anti-tumor ability of this combined immune checkpoint therapy.

Fig.2 Improved enrichment and excitation of CD8⁺ T cells and NK cells are keys for combined therapy-mediated tumor regression.²

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References

1. Greenberg, Steven A., et al. "Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models." Oncotarget 10.14 (2019): 1399.
2. Tata, Angela, et al. "Combination blockade of KLRG1 and PD-1 promotes immune control of local and disseminated cancers." Oncoimmunology 10.1 (2021): 1933808.

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