An epigenetic modifier triggers therapeutic immune responses against breast cancer

KEYWORDS:

• CD8⁺ cytotoxic T cells
• chemotherapy
• immune checkpoint blockade
• PD-1
• TMP195
• tumor-associated macrophages

Preclinical and clinical evidence accumulating over the past decade suggests that tumor-associated macrophages (TAMs) generally promote disease progression and resistance to treatment by virtue of their pronounced angiogenic and immunosuppressive effects.^1,2 Accordingly, several strategies have been developed to deplete TAMs, inhibit their tumor-supporting activity, or reprogram them toward a phenotypic and functional state that is normally observed in the context of infectious disorders.³ Promising preclinical results in this sense have been obtained with small molecules that inhibit colony stimulating factor 1 receptor (CSF1R, also known as CD115), notably PLX-3397.^4-6 As a result of these studies, PLX-3397 is currently being evaluated in combination with conventional chemotherapy or radiation therapy for use in patients affected by multiple neoplasms.^7,8 Very recently, the research team led by Anthony Letai (from Dana-Farber Cancer Institute, Boston, MA, USA) has demonstrated that an inhibitor of class IIa histone deacetylases (HDACs) promotes the recruitment of inflammatory macrophages to experimental breast carcinomas, resulting in the initiation of a therapeutically relevant immune response.⁹ These findings may pave the way to novel strategies for unleashing the anticancer potential of TAMs based on selective epigenetic modifications.

Upon identifying that a selective inhibitor of class IIa HDACs, namely, TMP195, alters gene expression in monocytes, but virtually does not affect lymphocytes, Letai and collaborators set out to investigate the effects of this agent in MMTV-PyMT transgenic mice, an endogenous model of luminal type B breast carcinoma in which tumor progression (including metastatic dissemination) is largely dependent on CSF1R and macrophages.^10,11 Intraperitoneal administration of TMP195 as a standalone therapeutic intervention increased the proportion of tumor-infiltrating CD11b⁺ myeloid cells and cells with markers of mature macrophages including CSF1R, galectin 3 (LGALS3, also known as Mac-2), mannose receptor C-type 1 (MRC1, also known as CD206) and adhesion G protein-coupled receptor E1 (ADGRE1, best known as F4/80). Conversely, TMP195 failed to affect the relative intratumoral abundance of B cells (CD19⁺ cells), T cells (CD3⁺, CD4⁺, and CD8⁺ cells), natural killer cells (NK1.1⁺ cells), and cells with granulocytic markers such as Ly6C and Ly6G. Interestingly, the accumulation of mature macrophages within TMP195-treated tumors almost completely reflected the recruitment of new monocytes from the circulation and was accompanied by a relative decrease in immunosuppressive CD11b^lowMHCII⁺ TAMs. Moreover, TMP195 administration to mice bearing endogenous MMTV-PyMT-driven mammary carcinomas was associated with increased abundance of tumor-infiltrating CD40⁺ cells, vasculature normalization, cancer cell death, phagocytosis of apoptotic bodies, and expression of granzyme B by local CD8⁺ cytotoxic T lymphocytes (whose abundance, though, remained unaltered). In vitro, however, TMP195 failed to affect the viability and proliferation rate of multiple mammary carcinoma cell lines.⁹ Altogether, these findings suggest that TMP195 endows the myeloid tumor microenvironment with immunostimulatory functions and limits its capacity to support abnormal angiogenesis.

Intraperitoneal TMP195 administered as a standalone treatment virtually abolished the growth of endogenous MMTV-PyMT-driven mammary carcinomas as well as their capacity to form metastases. Such a prominent anticancer activity depended on macrophages, CD8⁺ cytotoxic T lymphocytes (but not CD4⁺ T cells), and interferon gamma (IFNγ) secretion, as demonstrated in experiments based on specific depleting or neutralizing antibodies, or performed in athymic Foxn1^nu mice xenografted with MMTV-PyMT-driven mammary carcinomas (a model in which paclitaxel-based chemotherapy had antineoplastic effects). Accordingly, systemic IFNγ neutralization prevented TMP195 from inducing the intratumoral accumulation of GRZB⁺CD8⁺ cytotoxic T cells and vascular normalization within malignant lesions. Finally, TMP195 considerably ameliorated the efficacy of paclitaxel-based chemotherapy, carboplatin-based chemotherapy, and immune checkpoint blockade with a monoclonal antibody targeting programmed cell death 1 (PDCD1, best known as PD-1) against endogenous MMTV-PyMT-driven mammary carcinomas.⁹ These data suggest that TMP195 mediates anticancer effects by virtue of its ability to alter the myeloid tumor microenvironment.

Altogether, the findings by Letai and collaborators delineate a new strategy to potentially harness the anticancer activity of TAMs, which appears to rely on systemic reprogramming of the myeloid compartment. Several uncertainties remain to be addressed. First, which is the primary systemic target of TMP195 that is responsible for the recruitment of new macrophages with antineoplastic activity to the tumor bed? At is stands, neither the bone marrow nor a rather heterogeneous circulating population of immature myeloid cells with immunosuppressive activity, cumulatively known as myeloid-derived suppressor cells (MDSCs), can be formally excluded as source of TMP195-induced TAMs. Second, does TMP195 mediate anticancer effects in settings in which the tumor-supporting functions of macrophages are less prominent than in MMTV-PyMT-driven mammary carcinomas? Third, to which extent are malignant cells exposed to TMP195 responsible for its capacity to alter the myeloid tumor compartment? Addressing these and other questions related to the immunomodulatory activity of TMP195 (or similar drugs) will provide additional insights into the possibility of using epigenetic modifiers to increase the efficacy of chemo-, radio-, or immunotherapy.

Disclosure of potential conflicts of interest

LG provides remunerated consulting to OmniSEQ (Buffalo, NY, USA).