Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade

Publication date: April 2019

Source: Oral Oncology, Volume 91

Author(s): Hidetake Tachinami, Naoto Nishii, Yulong Xia, Yoshihisa Kashima, Tatsukuni Ohno, Shigenori Nagai, Lixin Li, Walter Lau, Kei Tomihara, Makoto Noguchi, Miyuki Azuma

Abstract

Objectives

The immune status of the tumor microenvironment has a marked impact on clinical outcomes. Here we examined the immune environments of tumor-infiltrating leukocytes (TILes) in two murine models of squamous cell carcinoma and compared the effects of immunotherapeutic agents, including a TLR7 agonist and an immune checkpoint inhibitor, and a chemotherapeutic agent, gemcitabine, in these models.

Materials and methods

TILes from NR-S1- and SCCVII-grafted mice were analyzed by flow cytometry. NR-S1-inoculated mice received resiquimod (a synthetic TLR7 agonist), an anti-PD-L1 antibody, or both, and tumor growth and TILs were examined. Gemcitabine was administered to deplete CD11b⁺ cells.

Results

More than 50% of TILes from NR-S1- and SCCVII-inoculated mice were CD11b⁺Gr-1⁺ cells. A major fraction of NR-S1 CD11b⁺ cells was Ly6G^highLy6C^low-negaF4/80⁻ tumor-associated neutrophils (TANs) and the majority of SCCVII CD11b⁺ cells were Ly6G^lowLy6C⁻F4/80⁺ tumor-associated macrophages. NR-S1 TANs did not express MHC class II and CD86, but did express reactive oxygen species and PD-L1. Resiquimod, alone and in combination with an anti-PD-L1 antibody, did not regress NR-S1 tumors, but the combination increased the CD8/regulatory T cell-ratio, and IFN-γ and PD-1 expression in CD8⁺ TILes. Pre-administration of low-dose gemcitabine prior to the combination treatment suppressed the progression of NR-S1 tumors.

Conclusions

NR-S1 tumors with abundant recruitment of TANs were resistant to treatments with a TLR7 agonist, alone and in combination with PD-1 blockade, and required an additional gemcitabine treatment. The phenotype and status of tumor-infiltrating CD11b⁺ myeloid cells may influence the efficacy of immunotherapeutic agents.

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