Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer

Abstract

Host responses to tumor cells include tumor suppressing or promoting mechanisms. We sought to detail the effect of Hedgehog (Hh) pathway inhibition on the composition of the mammary tumor immune portfolio. We hypothesized that Hh signaling mediates a crosstalk between breast cancer cells and macrophages that dictates alternative polarization of macrophages and consequently supports a tumor-promoting microenvironment. We used an immunocompetent, syngeneic mouse mammary cancer model to inhibit Hh signaling with the pharmacological inhibitor, Vismodegib. Using molecular and functional assays, we identified that Hedgehog (Hh) signaling mediates a molecular crosstalk between mammary cancer cells and macrophages that culminates in alternative polarization of macrophages. We carried out an unbiased kinomics and genomics assessment to unravel changes in global kinomic and gene signatures impacted by Hh signaling. Our investigations reveal that in an immunocompetent mammary cancer model, the administration of Vismodegib led to changes in the portfolio of tumor-infiltrating immune cells. This was characterized by a marked reduction in immune-suppressive innate and adaptive cells concomitant with an enrichment of cytotoxic immune cells. Breast cancer cells induce M2 polarization of macrophages via a crosstalk mediated by Hh ligands that alters critical kinomic and genomic signatures. Macrophage depletion improved the benefit of Hedgehog inhibition on eliciting an immunogenic, pro-inflammatory profile. We define a novel role for Hh signaling in disabling anti-tumor immunity. Inhibition of Hh signaling presents with dual advantages of tumor cell-targeting as well as re-educating a dysfunctional tumor microenvironment.

Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment

“…Although a recent report has suggested a role for lactic acid in functional polarization of TAMs (14), the molecular pathways required for TAM M2 polarization in vivo remain largely unknown. A previous study has implicated the important role of Hh signaling in reprogramming the TME to facilitate tumorigenesis through TAMs in breast cancer (38). Our observations provided further evidence that the Hh signaling pathway in TAMs is critical for their M2 polarization to promote tumorigenesis.…”

An Exploratory Gene Expression Study of the Intestinal Mucosa of Patients with Non-Celiac Wheat Sensitivity

“…Besides immunity, ingenuity pathway analysis (IPA) suggested that the hedgehog pathway might have a role in NCWS. It is worthwhile to mention that a few studies demonstrated the involvement of hedgehog pathway in celiac disease and alteration of immune surveillance in cancer development [45][46][47].…”

The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas

“…Conversely, M2 macrophages are stimulated by Th2 cytokines such as transforming growth factor β 1 (TGF-β 1 ), IL-4 and IL-13 [87], which activate STAT6 target genes [88] (suppressing immune system functions) and promote tumor cell proliferation. M2 TAMs are the most frequent type in breast cancers [89] since during carcinogenesis TME most likely drives M1 to the M2 phenotype [90]. It is well known that macrophages are recruited to the tumor by a range of chemokines (including vascular endothelial growth factor, VEGF, and C-C chemokine ligand 2) and foster breast cancer progression in different ways: regulating stroma invasion and cell intravasation [91,92], promoting angiogenesis [93] and metastasis [94,95], and remodeling extracellular matrix (ECM) by metalloproteinase secretion [96].…”