Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell–mediated tumor regression

Abstract

Tumor-associated macrophages (TAMs) play critical roles in tumor progression but are also capable of contributing to antitumor immunity. Recent studies have revealed an unprecedented heterogeneity among TAMs in both human cancer and experimental models. Nevertheless, we still understand little about the contribution of different TAM subsets to tumor progression. Here, we demonstrate that CD163-expressing TAMs specifically maintain immune suppression in an experimental model of melanoma that is resistant to anti–PD-1 checkpoint therapy. Specific depletion of the CD163+ macrophages results in a massive infiltration of activated T cells and tumor regression. Importantly, the infiltration of cytotoxic T cells was accompanied by the mobilization of inflammatory monocytes that significantly contributed to tumor regression. Thus, the specific targeting of CD163+ TAMs reeducates the tumor immune microenvironment and promotes both myeloid and T cell–mediated antitumor immunity, illustrating the importance of selective targeting of tumor-associated myeloid cells in a therapeutic context.

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

“…44 In addition, in a melanoma tumor model, the depletion of CD163 + TAMs, using an anti-CD163 antibody conjugated to a doxorubicin charged liposome, led to a monocyte influx, the up-regulation of IFN-related cytokines and an anti-tumor T-cell response. 45 Importantly, we described for the first time that conditioned-media supernatants of dilacerated primary human breast tumors promote either highly suppressive CD163 high IL-10 high CD86 low MΦ, resembling suppressive TAMs, [46][47][48] or CD163 low IL-10 low CD86 low MΦ, displaying moderate suppressive functions. Aside from its central role in T-cell suppression, we further documented the contribution of autocrine IL-10 in the phenotypic/ functional switch of monocytes into suppressive CD163 high MΦ, with low IL-12p40 production and high PD-L1 expression, in accordance with previous reports.…”

“…In a murine colon adenocarcinoma model, treatment with two mAbs to concomitantly block CSF‐1R and stimulate CD40 resulted in the reprogramming of TAMs by increasing pro‐inflammatory signals such as IL‐12B, IL‐27, IL‐1β and CCL5 . In addition, in a melanoma tumor model, the depletion of CD163 + TAMs, using an anti‐CD163 antibody conjugated to a doxorubicin charged liposome, led to a monocyte influx, the up‐regulation of IFN‐related cytokines and an anti‐tumor T‐cell response …”

Ratio of the interferon-γsignature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma

“…The dense collagen matrix produced by CAFs may also present a physical barrier to the infiltration of T lymphocytes 57 or treatments reaching the cancer cells 58 . Indeed, the association between a lack of response to ICIs and upregulated EMT-related genes has been observed in multiple cancers 40,59 , and inhibiting CAF/TAM-related pathways and extracellular collagen and hyaluronan can induce T cell accumulation and improve the outcome of ICIs [60][61][62][63] , reinforcing the role of those stromal-related activities in limiting the efficacy of immune checkpoint blockade immunotherapy.…”

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

“…We focused in particular on macrophages whose function can be modulated by the sympathetic nervous system in several organs and disease contexts 25 . To label macrophages in pancreatic sections of chemically sympathectomized or control KIC mice, we used the macrophage-specific markers F4/80 and CD163, the latter being frequently observed in aggressive tumors 26 . All cells expressing the surface receptor CD163 were also F4/80 + and accounted for nearly half of the macrophages found in asymptomatic pancreas regions ( Supplementary Fig.…”