In the 19th century, Rudolf Virchow, often referred to as the father of modern pathology, noted the presence of leukocytes within tumor specimens, raising the possibility of a connection between inflammation and cancer [1]. However, as is often the case in biomedical sciences, the link between cancer and inflammation went largely unnoticed until about a decade ago when the NF-kappaB signaling pathway emerged as a significant contributor to cancer growth and development. NF-kappaB plays a crucial role in enabling pre-neoplastic and malignant cells to evade apoptosis-based tumor-surveillance mechanisms, thereby establishing a mechanistic connection between inflammation and cancer [2]. Myeloid inflammation can promote tumor progression through both direct and indirect effects on T cell activity. In clinical practice, the neutrophil-to-lymphocyte ratio (NLR), reflecting myeloid inflammatory activation, is gaining importance as a prognostic indicator in various oncological conditions [3].

In recent years, prostate cancer has emerged as one of the most significant players in the field of personalized medicine [4]. Specifically, the clinical management of metastatic castration-resistant prostate cancer (mCRPCa), which previously had a bleak prognosis and limited therapeutic options, has been revolutionized by the introduction of novel treatments [4]. These treatments range from androgen receptor signaling inhibitors (ARSI) to more recently introduced radioligand therapies that target the prostate-specific membrane antigen (PSMA) [4]. However, therapies aimed at inducing T-cell-mediated immunity seem to have limited efficacy in mCRPCa, as discussed in the recent ESMO congress in 2023 (KEYNOTE 641). The limited efficacy can be attributed to the low presence of T cells and the frequent infiltration of immunosuppressive myeloid cells (CD11b + HLA-DRloCD15 + CD14-). Notably, an elevated NLR has been linked to a poor prognosis and resistance to ARSI in mCRPCa, prompting the exploration of alternative receptors capable of eliciting a response to non-self-elements.

In this scenario, the recent paper published by Guo et al. in the scientific journal Nature has significantly advanced our understanding of the relationship between myeloid inflammation and prostate cancer, while also opening up new possibilities for translational research [5]. Building upon preclinical evidence suggesting that the recruitment of myeloid cells into prostate cancer is influenced by tumor-derived chemokines binding to the C-X-C motif chemokine receptor-2 (CXCR2); the authors hypothesized that myeloid inflammation could be regulated by CXCR2-related chemokines secreted by human prostate cancer. They also proposed that targeting CXCR2 might potentially reverse and overcome resistance to ARSI.

In the initial phase of their study, the authors validated the relationship between CD11b + HLADRloCD15 + CD14- myeloid cell density and peripheral blood NLR, as well as neutrophil count, in a cohort of 57 individuals affected by mCRPCa. Subsequently, the authors discovered that several ligands for CXCR2, namely, CXCL1, CXCL2, and CXCL8, were positively associated with an increased NLR. Furthermore, molecules implicated in the CXCR-2 axis, such as CXCL1-3, CXCL5, CXCL6, and CXCL8, exhibited a negative correlation with overall survival from the time of mCRPCa biopsy. Notably, in the examined cohorts, CXCR2 was expressed by the majority of CD11b + HLADRloCD15 + CD14- cells in CRPC specimens, regardless of the biopsy sites.

The translational phase of the study is, from the clinicians’ perspective, the most intriguing part of the research. The authors administered a CXCR2 inhibitor (CXCR2i), specifically AZD5069 tested also in coronary artery disease [6], in combination with enzalutamide to patients with mCRPCa who had progressed after at least one cycle of ARSI treatment. Among the 21 enrolled patients, no dose-limiting toxicity (DLT) was observed, with the most frequent adverse event being grade 3 neutropenia. Notably, AZD5069 led to a dose-dependent decrease in blood neutrophil counts and NLR. More importantly, CXCR2 was capable of reducing myeloid cell infiltration, as measured in pre- and on-treatment biopsies obtained from the same disease sites. Out of the 21 enrolled patients, five (24%) exhibited an objective partial response according to pre-defined response criteria, which included a ≥ 30% decrease in measurable disease, a ≥ 50% decrease in PSA value, and the conversion of circulating tumor cells. Patients needed to remain on treatment for at least 12 weeks to be classified as responders.

The research conducted by Guo et al. [5] represents an elegant scientific inquiry while also demonstrating how well-executed laboratory research can translate from the bench to the patient's bedside, yielding significant clinical implications, as shown in Fig. 1. At the same time, some possible future developments of this research deserve further discussion.

Fig. 1
figure 1

Schematic representation of the interaction between prostate carcinoma (on the left), cytokines, and myeloid cells (on the right). The use of the CXCR2 inhibitor blocks the mechanism of myeloid cell recruitment within the tumor (illustration is authors’ own work, created with Biorender.com)

Full size image

The potential implementation of a treatment targeting the CXCR2 axis would require a robust, accessible, and reproducible method for detecting and quantifying the mentioned biomarker in mCRPCa patients. While biopsies are commonly used for the initial assessment, they have several limitations. They are invasive, requiring multiple procedures at various disease sites to investigate biomarker expression heterogeneity. Biopsies also need to be repeated during treatment to detect the emergence of acquired resistance during targeted therapy. Alternatively, molecular imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT) with radiolabeled imaging probes can be considered. This approach has the capability to accurately detect and quantify tumor-associated biomarkers and can be repeated over time to reveal acquired resistance to therapy [7]. Since chemokines and chemokine receptors have been identified as critical components in regulating immune cell functions, numerous endeavors have been undertaken to develop radiopharmaceuticals suitable for PET imaging of pathways involving chemokines [8]. In particular, [68 Ga]-Pentixafor, a synthetic ligand for chemokine receptor 4 (CXCR4), has been introduced as a promising tool for PET imaging of various solid and hematologic malignancies, yielding particularly encouraging results in the case of multiple myeloma [9]. On the same research path, [99mTc]Tc-CXCL8 has been synthesized and effectively employed for imaging CXCR-1 and CXCR-2 mediated neutrophil trafficking in inflammatory conditions [10]. In pre-clinical studies, [99mTc]Tc-CXCL8 SPECT has demonstrated promising initial results in targeting neutrophil recruitment to the intestinal wall, particularly during moderate to severe exacerbations of inflammatory bowel disease [11]. Nonetheless, it is widely recognized that SPECT has several limitations in terms of spatial resolution, accuracy, and its ability to provide precise quantitative measurements. While the recent introduction of whole-body SPECT/CT, equipped with highly advanced CZT detectors, has advanced the field, PET boasts superior diagnostic performance and enables accurate quantitative analysis. Furthermore, the modern long axial field-of-view PET/CT (LAFOV PET/CT) has significantly expanded the applications of this imaging method in oncology, enabling dynamic acquisitions for pharmacokinetic studies [12]. To the best of our knowledge, there is currently no scientific literature available that specifically focuses on tracers targeting CXCR2, although it seems very promising.

The research from Guo’s group [5] further emphasize the crucial role of CXCR in cancer. In light of these findings, it is imperative to intensify our efforts through a strategic synergy between technology and radiopharmacy to develop new tracers for PET studies of CXCR2. This approach can open new horizons for potential theranostic applications using appropriate radionuclides emitting beta or alpha particles.