Combined Therapy of PD-L1 and TGF-β

Immune checkpoint molecules are increasingly being recognized as targets for immunotherapy against cancer. Though programmed death ligand 1 (PD-L1) antibodies show excellent and long-lasting responses during treatment, it is not effective for all tumor types and only works in a small percentage of patients. Transforming growth factor-β (TGF-β) is a cytokine that suppresses immune response and is frequently generated in high concentrations by a variety of cell types in the tumor microenvironment, which is well documented for its pleiotropic activity in beginning and encouraging tumor formation. The combination inhibition of PD-L1 and TGF-β has confirmed the advanced anticancer impact in recent studies.

Case 1: Combined Therapy Toward Mammary Carcinoma Model

The treatment of anti-TGF-β blocking the TGF-β receptor shows no antitumor effect in the EMT6 mouse mammary carcinoma model with an immune-excluded phenotype. The highest therapeutic effectiveness is shown in combination therapy with anti-PD-L1 antibody, which obviously decreases the tumor growth than anti-PD-L1 antibody alone. Based on the combined therapy, an increased infiltration of CD3⁺ and CD8⁺ T cells is observed in the tumor microenvironment, which is highly associated with reduced tumor volume and does not occur in monotherapy. These findings imply that TGF-β inhibition can enhance anti-tumor immunity by potentiating the effects of anti-PD-L1, leading to subsequent tumor regression.

Fig.1 Combined therapy leads to reduced tumor size and more tumor-infiltrating T cells.¹

Case 2: Combination Inhibition on Colon Carcinoma Model

In the mice bearing human PD-L1-expressing colon carcinoma tumors, the anti-PD-L1 antibody can significantly limit tumor growth, which is further enhanced by the combination inhibition with anti-TGF-β, leading to a 66.7% tumor regression. Furthermore, anti-TGF-β increases the anti-PD-L1-induced improved survival compared with the control group. When investigating the T cell infiltration, CD3 immunohistochemistry shows that the PD-L1 plus TGF-β blockade significantly increases T cell infiltration.

Fig.2 Combined therapy of anti-PD-L1 plus anti-TGF-β results in reduced tumor volume, increasing survival and T cell influx.²

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References

1. Mariathasan, Sanjeev, et al. "TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells." Nature 554.7693 (2018): 544-548.
2. Lim, Yoong Wearn, et al. "Single-cell transcriptomics reveals the effect of PD-L1/TGF-β blockade on the tumor microenvironment." BMC biology 19.1 (2021): 1-17.

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