Macrophage IL-10 Blocks CD8+ T Cell-Dependent Responses to Chemotherapy by Suppressing IL-12 Expression in Intratumoral Dendritic Cells

Abstract

Summary Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8+ T cell-dependent, however IL-10 did not directly suppress CD8+ T cells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…We showed that the adaptive immune system is dispensable for response to oxaliplatin, doxorubicin and cisplatin [85]. In line with these data, depletion of CD8 + T cells in MMTV-PyMT mammary tumor-bearing mice fails to counteract the efficacy of paclitaxel [22,23], indicating that CD8 + T cells are also dispensable in this experimental setting. Additionally, CD8 + T cell depletion in combination with 5-FU treatment of subcutaneous EL4 thymomas has no impact on tumor growth [56].…”

“…Paclitaxel treatment of mammary tumor-bearing MMTVPyMT mice increases TAM infiltration into tumors. These cells counteract chemotherapy efficacy via several mechanisms, including inhibition of anti-tumor CD8 + T cell responses via IL10-mediated suppression of dendritic cells [22,23], as well as secretion of chemoprotective 4 survival signals, such as cathepsins [24]. Interestingly, splenic macrophages have also been implicated in conferring systemic resistance to cisplatin in subcutaneous cell line models via secretion of lysophospholipids that alter DNA damage response [25].…”

“…The most common strategy used to date involves the inhibition of CSF1-CSF1R signaling, since these molecules are required for macrophage differentiation and maturation [26,27]. Paclitaxel treatment in combination with a CSF1R inhibitor reduces tumor growth in both MMTV-PyMT and C3(1)-Tag mice [22,23] -a conditional GEMM driven by SV40 large T antigen in mammary epithelial cells [28]. Of note, this therapy combination also decreases spontaneous lung metastasis in MMTV-PyMT mice, while neither paclitaxel nor CSF1R inhibitor alone affects metastasis formation [22,23].…”

“…However, another promising strategy that may prevent resistance to TAM depletion is to switch the polarization of TAMs from a pro- Anti-tumor immunity can be reinstated by combining paclitaxel with TAM depletion or neutralization of their tolerizing abilities (i.e. blocking IL10) [23]. While these studies report that the CD11b -dendritic cell subset is important for chemotherapy response in MMTVPyMT mammary tumors [23,62], the CD11b + subset plays a greater role in chemotherapyinduced immunogenic cell death of transplantable models [43].…”

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…The IL-10:IL-12 axis has been recently identified as an important indicator of chemotherapeutic responses, with IL-10 shown to limit subsequent intratumoral cytotoxic T-cell activity. 44 Moreover, a lower IL-12:IL-10 ratio is a negative prognostic marker, indicative of a suboptimal immune response in HPV-associated pre-neoplastic lesions. 45 In addition, IL-12 is a key Th1 promoting cytokine, which may underlie the enhanced IFNγ production observed in vistusertib/αCTLA-4 treated tumours.…”