Abstract 2726: Host myeloid response drives anti-PD-L1 resistance in murine models of triple negative breast cancer
Authors: Hanna Ann , Sun Xiaopeng , Gonzalez-Ericsson Paula I. , Sanchez Violeta , Balko Justin M. 
Published: June 2022

Immune checkpoint inhibitors (ICI) have improved patient overall and progression-free survival in some cancer types with limited success in breast cancer. Clinical trials in triple negative breast cancer (TNBC) patients, who harbor extensive tumor-infiltrating lymphocytes within tumor stroma, have demonstrated increased progression-free survival (IMpassion130) and pathologic complete response (KEYNOTE-522). Thus, combinations of ICI and chemotherapy have been FDA-approved for metastatic TNBC. However, the therapeutic benefit of ICI alone is poorly characterized. We sought to model ICI response in vivo to ascertain the immune repertoire responsible for ICI efficacy in breast cancer and identify the therapeutic benefit of ICI alone or in combination with approved chemotherapeutics.

We used an immunocompetent EMT6 orthotopic mammary tumor model to investigate the efficacy of single-agent ICI (anti-PD-L1) or in combination with standard-of-care chemotherapy (paclitaxel or doxorubicin). Analysis of the primary tumor immune landscape was performed by flow cytometry and single-cell RNA sequencing. Peripheral blood from mice was serially sampled by bulk and T-cell receptor (TCR) sequencing to identify systemic genomic alterations and T-cell expansion, respectively.

Single-agent ICI robustly suppressed primary tumor growth (p =0.0046) and extended survival (p&lt;0.0001) beyond the control group. While chemotherapy demonstrated moderate therapeutic efficacy, it did not enhance ICI benefit. Transcriptomic and phenotypic profiling of the tumor microenvironment (TME) revealed increased T cells, dendritic cells, and NK cells in the combination groups versus chemotherapy alone, but this did not translate into improved benefit. Interestingly, despite using a genetically identical tumor model and murine host, ICI induced heterogeneous responses, ranging from complete response to intrinsic resistance. The longitudinal analysis of peripheral blood from heterogeneously responding mice uncovered enriched myeloid signatures and clonal T cell expansion corresponding to ICI resistance and response, respectively.

In conclusion, we identify a heterogeneously ICI-responsive in vivo model that emulates TNBC patient response to combinatorial ICI approaches. We report the efficacy of single-agent ICI in upregulating cytotoxic immune cell infiltration and expansion within the primary tumor, thereby diminishing tumor growth and enhancing survival. We describe host-specific signatures, specifically myeloid cells, that correlate with differential responses to immunotherapy, which models heterogeneous patient response to ICI. Ongoing characterization of matched peripheral blood and TME samples may identify systemic biomarkers and tumor antigen-specific T cell clones to accurately predict ICI response in patients and uncover mechanisms for sensitizing tumors refractory to ICI.

Citation Format: Ann Hanna, Xiaopeng Sun, Paula I. Gonzalez-Ericsson, Violeta Sanchez, Justin M. Balko. Host myeloid response drives anti-PD-L1 resistance in murine models of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2726.