Blockade of p38 kinase impedes the mobilization of protumorigenic myeloid populations to impact breast cancer metastasis

Abstract

Patients with metastatic breast cancer (MBC) have limited therapeutic options and novel treatments are critically needed. Prior research implicates tumor‐induced mobilization of myeloid cell populations in metastatic progression, as well as being an unfavorable outcome in MBC; however, the underlying mechanisms for these relationships remain unknown. Here, we provide evidence for a novel mechanism by which p38 promotes metastasis. Using triple‐negative breast cancer models, we showed that a selective inhibitor of p38 (p38i) significantly reduced tumor growth, angiogenesis, and lung metastasis. Importantly, p38i decreased the accumulation of myeloid populations, namely, myeloid‐derived suppressor cells (MDSCs) and CD163+ tumor‐associated macrophages (TAMs). p38 controlled the expression of tumor‐derived chemokines/cytokines that facilitated the recruitment of protumor myeloid populations. Depletion of MDSCs was accompanied by reduced TAM infiltration and phenocopied the antimetastatic effects of p38i. Reciprocally, p38i increased tumor infiltration by cytotoxic CD8+ T cells. Furthermore, the CD163+/CD8+ expression ratio inversely correlated with metastasis‐free survival in breast cancer, suggesting that targeting p38 may improve clinical outcomes. Overall, our study highlights a previously unknown p38‐driven pathway as a therapeutic target in MBC.

Diversity and versatility of p38 kinase signalling in health and disease

“…Furthermore, non-canonical p38α activation in T cells promotes an inflammatory state that facilitates pancreatic ductal carcinoma development 228 . In addition, cancer cells also rely on p38α to produce cytokines and chemokines that recruit pro-tumorigenic myeloid cells to the tumour niche 229 . Similarly, the p38α–MK2 axis was implicated in the upregulation of T cell inhibitory protein PDL1 in cancer cells favouring immune suppression signalling 71 .…”

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

“…p38 inhibition improves not only the persistence and tumor infiltration of T cells that results in their boosted antitumor activity but also enhances the functionalities of gene-engineered T cells (with TCR or CAR) [ 159 ]. Moreover, the p38 kinase inhibition increases the abundance of cytotoxic CD8 + T cells and their tumor infiltration [ 160 ]. miRNA-5119 expressing DCs downregulate PD-L1 and not only prevent exhaustion of CD8 + T cells but also restore the antitumor activity of exhausted T cells and increase their proliferation [ 161 ].…”

Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

“…The prevention and treatment of cancer metastasis remain to be a great challenge. Pharmacological inhibition of p38MAPK may suppress the metastasis of breast cancer and melanoma 46 , 47 . The oral p38MAPK inhibitor ralimetinib (LY2228820) has undergone clinical trials and demonstrated acceptable tolerability 48 .…”