Exploring The Contribution of Innate Immune Cells to Breast Cancer Immunotherapy

Spatial Analysis of Tumor-Infiltrating Immune Cells with Multiplex RNAscope

Abstract

Breast cancer is the leading type of cancer in women. About 10% to 15% of breast cancers are triple-negative breast cancer (TNBC), a subtype with the worst prognosis. Due to the lack of estrogen, progesterone, and HER2 receptor expression, chemotherapies have been the standard of care for decades. Immunotherapy has emerged as promising for TNBC treatment. In 2020, the Food and Drug Administration (FDA) granted approval to Pembrolizumab in combination with chemotherapy for patients with advanced triple-negative breast cancer. However, only a subgroup of advanced TNBC patients lived longer than those whose tumors have a PD-L1 Combined Positive Score of at least 10 (CPS≥10). There is still an unmet medical need to provide alternative treatment for the rest of patients.

Interestingly, a few of the patients at UCSD Moores Cancer Center had excellent responses to Pembrolizumab despite low CPS scores (termed Elite Responders). There may be an alternative immune response mechanism and/or crosstalk happening between the innate and adaptive immune systems that contributed to this unexpected excellent response, especially in Natural Killer Cells and Macrophages. Our procedure used ACDBio RNAscope Multiplex Fluorescence v2 method to spatially analyze innate immune cells (Natural Killer cells and macrophages) and adaptive immune cells (T cells) in the tumor microenvironment. Our data demonstrated increased tumor infiltration of innate immune cells (Macrophages and Natural Killer cells) in the Elite Responders. This conclusion indicated the joint effort of two immune systems (innate and adaptive) which eventually led to increased survival.

Keywords: Triple Negative Breast Cancer (TNBC), Natural Killer cells (NKs), Immune Checkpoint Blockades (ICB), Programmed Death-Ligand 1 (PD-L1), Programmed Cell Death Protein 1 (PD1), Tumor Microenvironment (TME)