Evolutionary exploitation of PD-L1 expression in hormone receptor positive breast cancer

Abstract

Figure 1: Representative results from the three models. Top left: A game-theoretic model uses trajectories (blue) through the expression space of CCR7 and PD-L1 under AI therapy to predict cumulative metastatic potential (red gradient). Top right: A cellular automaton model examines the possible mechanisms for inducing CCR7 expression, comparing spatial heterogeneity patterns with those seen in biopsies. Bottom: An ODE model predicts the improvement in PEPI score following combination AI and CI therapy.Abstract-Based on clinical data from hormone positive breast cancer patients, we determined that there is a potential tradeoff between reducing tumor burden and altering metastatic potential when administering combination therapy of aromatase inhibitors and immune checkpoint inhibitors. While hormone-deprivation therapies serve to reduce tumor size in the neoadjuvant setting pre-surgery, they may induce tumors to change expression patterns towards a metastatic phenotype. We used mathematical modeling to explore how the timing of the therapies affects tumor burden and metastatic potential with an eye toward developing a dynamic prognostic score and reducing both tumor size and risk of metastasis.

Effect of Primary Systemic Therapy on PD-1, PD-L1, and PD-L2 mRNA Expression in Advanced Breast Cancer

“…Treatment with tamoxifen is also increased PD-L1 expression in mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) breast cancer mice models (Hühn et al, 2019). It also has been shown that aromatase inhibitor (AI) therapy might increase the expression of both PD-L1 and chemokine receptor CCR7 in tumors (Turnbull et al, 2020;West et al, 2018). In a prostate cancer trial, enzalutamide plus pembrolizumab was associated with increased PD-L1 expression in tumor and dendritic cells, and increased PD-1-positive in circulating T-cells (Bishop et al, 2015;Graff et al, 2016).…”

“…In this study, aromatase inhibitor (AI), tamoxifen, and GnRH analogue are given to breast cancer patients. It has been reported that AI and tamoxifen could induce PD-L1 expression (Hühn et al, 2019;Turnbull et al, 2020;West et al, 2018). Meanwhile, the effect of GnRH analogs on PD-L1 expression is still unknown.…”