Tumor cells frequently produce soluble factors that favor myelopoiesis and recruitment of myeloid cells to the tumor microenvironment (TME). Consequently, the TME of many cancer types is characterized by high infiltration of monocytes, macrophages, dendritic cells and granulocytes. Experimental and clinical studies show that most myeloid cells are kept in an immature state in the TME. These studies further show that tumor-derived factors mold these myeloid cells into cells that support cancer initiation and progression, amongst others by enabling immune evasion, tumor cell survival, proliferation, migration and metastasis. The key role of myeloid cells in cancer is further evidenced by the fact that they negatively impact on virtually all types of cancer therapy. Therefore, tumor-associated myeloid cells have been designated as the culprits in cancer. We review myeloid cells in the TME with a focus on the mechanisms they exploit to support cancer cells. In addition, we provide an overview of approaches that are under investigation to deplete myeloid cells or redirect their function, as these hold promise to overcome resistance to current cancer therapies.

Targeted therapy and immunotherapy have become mainstream in cancer treatment. However, only patient subsets benefit from these expensive therapies, and often responses are short‐lived or coincide with side effects. A growing modality in precision oncology is the development of theranostics, as this enables patient selection, treatment and monitoring. In this approach, labeled compounds and an imaging technology are used to diagnose patients and select the best treatment option, whereas for therapy, related compounds are used to target cancer cells or the tumor stroma. In this context, nanobodies and nanobody-directed therapeutics have gained interest. This interest stems from their high antigen specificity, small size, ease of labeling and engineering, allowing specific imaging and design of therapies targeting antigens on tumor cells, immune cells as well as proteins in the tumor environment. This review provides a comprehensive overview on the state-of-the-art regarding the use of nanobodies as theranostics, and their importance in the emerging field of personalized medicine.

Mutations in TUBA1A have been described in patients with lissencephaly and pachygyria. We report a mutation in TUBA1A as a cause of polymicrogyria. So far, all mutations in TUBA1A have occurred de novo, resulting in isolated cases. This article describes familial recurrence of TUBA1A mutations due to somatic mosaicism in a parent. These findings broaden the phenotypic spectrum associated with TUBA1A mutations and have implications for genetic counseling.

Immune checkpoint inhibition (ICI) is a promising cancer therapy, which has progressed rapidly from a preclinical concept to clinical implementation. Commonly considered targets in ICI are CTLA-4, PD-1/PD-L1, and LAG-3, and the list grows. As ICI is generally only beneficial for a subset of patients, there is a need to select patients that are eligible for therapy as well as to monitor therapy response. There is growing interest to do this noninvasively, by molecular imaging with target-specific tracers. To this day, noninvasive imaging has focused on CTLA-4 and PD-1/PD-L1, while there is no noninvasive tool available to accurately assess LAG-3 expression in vivo. In this proof-of-concept study, we developed nanobodies, the smallest functional fragments from camelid heavy chain-only antibodies, to noninvasively evaluate mouse LAG-3 expression using single photon emission computed tomography (SPECT)/CT imaging. The in vitro characterization of 114 nanobodies led to the selection of nine nanobodies binding to mouse LAG-3. The injection of 99mTechnetium-labeled nanobodies in healthy mice showed specific uptake in immune peripheral organs like the spleen and lymph nodes, which was not observed in LAG-3 gene knock-out mice. Moreover, nanobody uptake could be visualized using SPECT/CT and correlated to the presence of LAG-3 as assessed in flow cytometry and immunohistochemistry. SPECT/CT scans of tumor bearing mice further confirmed the diagnostic potential of the nanobodies. These findings substantiate the approach to use nanobodies as a tool to image inhibitory immune checkpoints in the tumor environment.

Myeloid cells are critically involved in the pathophysiology of cancers. In the tumor microenvironment (TME), they comprise tumor-associated macrophages (TAMs), neutrophils (TANs), dendritic cells, and myeloid-derived suppressor cells, which are further subdivided into a monocytic subset and a granulocytic subset. Some of these myeloid cells, in particular TAMs and TANs, are divided into type 1 or type 2 cells, according to the paradigm of T helper type 1 or type 2 cells. Type 1-activated cells are generally characterized as cells that aid tumor rejection, while all other myeloid cells are shown to favor tumor progression. Moreover, these cells are often at the basis of resistance to various therapies. Much research has been devoted to study the biology of myeloid cells. This endeavor has proven to be challenging, as the markers used to categorize myeloid cells in the TME are not restricted to particular subsets. Also from a functional and metabolic point of view, myeloid cells share many features. Finally, myeloid cells are endowed with a certain level of plasticity, which further complicates studying them outside their environment. In this article, we challenge the exclusive use of cell markers to unambiguously identify myeloid cell subsets in the TME. We further propose to divide myeloid cells into myeloid regulatory or stimulatory cells according to their pro- or antitumor function, because we contend that for therapeutic purposes it is not targeting the cell subsets but rather targeting their protumor traits; hence, myeloid regulatory cells will push antitumor immunotherapy to the next level.