Deficiency of dendritic cell–expressed PD-L1 reduced tumor growth and increased T-cell infiltration.

  • Major Finding: Deficiency of dendritic cell–expressed PD-L1 reduced tumor growth and increased T-cell infiltration.

  • Concept: Although most PD-L1 was not from dendritic cells, further PD-L1 depletion did not affect tumor growth.

  • Impact: This work has implications for the mechanism underlying the efficacy of anti–PD-L1 and anti–PD-1.

Although the canonical PD-L1–PD-1 interaction relevant to immunotherapy features cancer cell–expressed PD-L1 and T cell–expressed PD-1, there is also evidence that PD-L1 expressed by tumor-infiltrating myeloid cells may play an important role. Oh and colleagues investigated this idea, first focusing on the potential significance of cis interactions between PD-L1 and B7-1, an activating ligand of CD28 not expressed by most tumor cells, on myeloid cells. Blocking cis PD-L1–B7-1 interactions increased PD-L1–PD-1 binding, resulting in slightly increased tumor growth in a mouse model of colon adenocarcinoma in which the tumor cells were deficient in PD-L1, a finding that may be attributable to an observed increase in tumor-infiltrating CD8+ T cells. Further investigation revealed that approximately 75% of the PD-L1 on myeloid cells in these tumors was found on CD11b+CD64+ macrophages, whereas only 2% of the immune cell–expressed PD-L1 arose from CD11c+MHCII+ dendritic cells. However, dendritic cell–expressed PD-L1 was critical for antitumor immunity: Mice with dendritic cell–specific PD-L1 deficiency exhibited substantially decreased tumor growth, an effect not observed when PD-L1 deficiency was induced in macrophages. Treatment of the mice with PD-L1 deficiency in dendritic cells with anti–PD-L1 to block any remaining PD-L1 interactions did not further reduce tumor growth, providing more evidence that it is dendritic cell–expressed PD-L1, not PD-L1 from other sources, that is most important in this context. Mechanistically, dendritic cell–specific PD-L1 deficiency caused increased infiltration of highly activated tumor-infiltrating CD8+ T cells. Collectively, these results support a key role for PD-L1 expressed by dendritic cells in antitumor immunity and hint that the therapeutic mechanism of immune-checkpoint blockade using anti–PD-L1 or anti–PD-1 may depend on this subset of tumor-infiltrating myeloid cells.

Oh SA, Wu DC, Cheung J, Navarro A, Xiong H, Cubas R, et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nat Cancer 2020 Jun 22 [Epub ahead of print].

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