PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• Immunotherapy utilizing programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) blocking antibodies is a cornerstone in treating various cancers.
• PD-L1 expression on tumor biopsies is often a prerequisite for patient selection in these therapies.
• The precise mechanisms underlying the efficacy of PD-1/PD-L1 blockade are still under investigation.

Purpose of the Study:

• To investigate the role of PD-L1 expression on both malignant and immune cells in the context of PD-1/PD-L1 blockade immunotherapy.
• To elucidate the contribution of PD-L1 on different cell types within the tumor microenvironment to therapeutic response.
• To compare the effects of targeting PD-L1 on cancer cells versus immune cells in preclinical models.

Main Methods:

• Generation of preclinical tumor models with specifically depleted PD-L1 expression on cancer cells.
• Assessment of tumor outgrowth and immune cell infiltration in response to PD-L1 blockade therapy.
• Analysis of PD-L1 expression on myeloid-infiltrating cells within the tumor microenvironment.
• Comparison of PD-1 blockade therapy with PD-L1 blockade therapy in these models.

Main Results:

• Absence of PD-L1 on cancer cells led to delayed tumor outgrowth, mediated by CD8+ T cells, highlighting PD-L1's immunosuppressive role.
• PD-L1 was significantly expressed on myeloid cells within the tumor microenvironment.
• Targeting stromal PD-L1 with blocking antibodies demonstrated an additional antitumor effect.
• Both PD-1 and PD-L1 blocking therapies yielded comparable results, indicating involvement of PD-L1 on both malignant and immune cells.

Conclusions:

• PD-L1 expression on both cancer cells and immune cells within the tumor microenvironment is critical for the mechanism of action of PD-1/PD-L1 blocking antibodies.
• These findings suggest that PD-L1 expression on immune cells, not just cancer cells, should be considered for patient selection in immunotherapy.
• The study provides crucial insights that may refine patient stratification for PD-1/PD-L1 blockade immunotherapies.