CD14⁺macrophage-like cells as the linchpin of cervical cancer perpetrated immune suppression and early metastatic spread: A new therapeutic lead?

Abstract

A number of studies point to an aberrant differentiation and accumulation of CD14 PD-L1 M2-macrophage-like cells in the microenvironment of cervical cancer, which promote immunosuppressive conditions and are associated with tumor invasion, angiogenesis and metastasis. Therapeutic targeting of these macrophages may tip the balance in favor of antitumor immunity. Cervical cancer is the fourth most common cancer among women worldwide and is caused by a persistent infection and subsequent integration of high-risk types of the human papillomavirus. Continuous expression of the viral oncoproteins E6 and E7 has been shown essential to maintain the transformed state of infected keratinocytes. As these non-self oncoproteins are immunogenic, cervical cancer requires a highly immune suppressed tumor microenvironment to metastasize through lymphovascular space invasion (LVSI) to the pelvic tumor-draining lymph nodes (TDLN). Unraveling the mechanisms underlying this immune suppression may uncover novel therapeutic targets aimed at loco-regional control of cervical cancer.

Nodal metastasis in cervical cancer occurs in clearly delineated fields of immune suppression in the pelvic lymph catchment area

“…Next to the high numbers of Tregs, HLA-DR + - and PD-L1 + myeloid cells, and low CD8 + T cell/Treg ratios in LN+, interestingly, also in a number of LN−, we found high Treg numbers and low CD8 + T cell/Treg ratios. The measured PD-L1 + cells are most likely M2 (CD163 + ) macrophages [ 7 ], originating from monocytes in the presence of IL-6, PGE2 and IL-10 [ 10 , 25 ].…”

“…In contrast to Tregs, PD-L1 + myeloid cells were more strictly associated with the presence of metastases. We hypothesize that primary tumors convert CD14 + monocytes into suppressive PD-L1 + M2-like macrophages [ 10 ], which are able to induce Treg expansion. Prior to metastasis, lymph nodes are conditioned by these Tregs to form a metastatic niche.…”

“…This immune suppression in metastatically involved lymph nodes will stand in the way of effective anti-tumor immunity and may have to be tackled before immunotherapy can be effective and halt metastatic spread. In particular PD-L1 expressed on tumor-associated M2-like macrophages may represent an attractive therapeutic target [ 7 , 10 ]. While systemic immune checkpoint blockade in cervical cancer is currently being explored in several clinical trials [ 11 ], more localized targeting of the microenvironment of cervical tumors and their TDLN may be even more effective while minimizing side effects [ 12 ].…”

‘DURVIT’: a phase-I trial of single low-dose durvalumab (Medi4736) IntraTumourally injected in cervical cancer: safety, toxicity and effect on the primary tumour- and lymph node microenvironment

“…In a comparative study of the immune status of all dissected cervical tumour-draining lymph nodes in five patients, we described that immunosuppression (identified as low CD8+ T cell/ FoxP3+ Treg ratios) may precede actual metastasis, creating niches in the tumour-draining lymphatic catchment area [ 28 ]. These results led to the hypothesis that tumour-associated PD-L1 positive macrophages expand Tregs which subsequently migrate to down-stream lymph nodes to create immune suppressed metastatic niches [ 29 ].…”

The Preoperative Peripheral Blood Monocyte Count Is Associated with Liver Metastasis and Overall Survival in Colorectal Cancer Patients

“…The peripheral blood monocyte count includes the number of regulatory dendritic cells (DCs), which contribute to immune suppression in cancer patients by activating and promoting the differentiation of regulatory CD4+CD25+ T cells. Thus, cancer patients with abnormally high peripheral blood monocyte counts have a poor prognosis, [ 6 , 7 ] and both tumour progression and metastasis have been linked to the degree of immune suppression[ 8 ]. However, the relationship between preoperative peripheral blood monocyte counts and CRLM was not clear.…”