CXCR2+ MDSCs promote breast cancer progression by inducing EMT and activated T cell exhaustion

Abstract

Although myeloid-derived suppressor cells (MDSCs) have been demonstrated to contribute to tumor initiation, progression and metastasis, however, which MDSC subsets are preferentially expanded and activated, and what’s the key molecular mechanism responsible for specific MDSC subsets in promoting tumor progression need to be fully addressed. Here we identify that Ly6GmiLy6CloCD11b+CXCR2+ subpopulation (named CXCR2+ MDSCs) are predominately expanded and recruited in systemic and local tumor microenvironment during breast cancer progression and metastasis. The proportion of CXCR2+ MDSCs is inversely correlated with the infiltration of CD4+ or CD8+ T cells. Besides, CXCR2+ MDSCs promote breast cancer growth and metastasis to lung and/or lymph node in vivo. Furthermore, CXCR2+ MDSCs induce epithelial mesenchymal transition (EMT) of breast cancer cells via IL-6. Moreover, CXCR2+ MDSCs upregulate the expression of immunosuppressive molecules programmed cell death protein 1(PD1), PD1 ligand 1 (PDL1), lymphocyte activation gene 3 protein (LAG3), cytotoxic T lymphocyte antigen 4 (CTLA4), and T cell immunoglobulin domain and mucin domain protein 3 (TIM3) on CD4+ or CD8+ T cells, and induce exhaustion of the activated T cells partially via IFN-γ. These results demonstrate that CXCR2+ MDSCs accelerate breast cancer progression via directly inducing cancer cell EMT and indirectly promoting T cell exhaustion, suggesting that CXCR2+ MDSCs may be a potential therapeutic target of breast cancer.

Myeloid derived suppressor cells contribute to the malignant progression of oral squamous cell carcinoma

“…Interestingly, we also indicated that OSCC associated MDSCs accelerated malignant progression of OSCC by enhancing EMT essential for epithelial tumor metastasis. In accordance with our results, researches have demonstrated that CXCR2 + MDSCs were predominately expanded and recruited in breast cancer and could boost EMT of breast cancer cells dependently on IL-6/STAT3 signaling [40]. And the elimination of MDSCs diminished tumor metastasis in breast carcinoma model [41].…”

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…Therefore, the absence of PTEN may reduce the infiltration of CD8 + T cells by upregulating VEGF, leading to resistance to PD-1 therapy [94]. MDSCs are negatively correlated with CD4 + and CD8 + T cell infiltration and are an important factor in decreased T cell infiltration [113]. Additionally, the presence of immunosuppressive tumor stroma, especially in some solid tumors, makes it difficult for T cells to infiltrate, limiting the efficacy of PD-1 blockade immunotherapy.…”

Bacillus Calmette–Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer

“…It has been shown that MDSCs have a close relationship with PD-L1/PD-1 axis and BCG immunotherapy. 23 , 24 It has been demonstrated that MDSCs could upregulate PD-1 expression in CD8 + T cells and induce activated T cell exhaustion, 23 and in addition, recent studies indicated that CD8 + T cell-to-MDSC balance was associated with the recurrence of BCa undergoing BCG immunotherapy. 24 Patients with a low CD8 + T cell/MDSC ratio showed high recurrence rate after intravesical BCG immunotherapy.…”