Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth

Despite significant progress in cancer diagnostics and development of novel therapeutic regimens, successful treatment of advanced forms of cancer is still a challenge and may require personalized therapeutic approaches. In this review, we analyzed major mechanisms responsible for tumor cells chemoresistance and emphasized that intratumor heterogeneity is a critical factor that limits efficiency of cancer treatment. Intratumor heterogeneity is caused by genomic instability in cancer cells, resulting in the selection of resistant clones. Moreover, cancer cells in solid tumors are surrounded by cellular and molecular microenvironment that actively influences tumor cell behavior. Local tumor microenvironment (TME) consisting of immune cells with diverse phenotypes and functions strongly contributes to intratumor heterogeneity and modulates responses to treatment. Thus, targeting specific components of TME is a novel treatment strategy that can improve the outcome of conventional anti-cancer therapy. Here, we discuss modern immunotherapeutic approaches based on targeting tumorinfiltrating immune cells including neutrophils, dendritic cells, NK cells, T cells, B cells and macrophages. Among those, tumor-associated macrophages (TAM) that display a pronounced heterogeneity and phenotypic plasticity appear to be a major component in the TME of solid tumors, and emerge as perspective targets for cancer immunotherapy. TAM intratumor heterogeneity and the possible existence of patient-specific phenotype signature generate the basis for the development of individualized TAM-based therapeutic approaches.

Circulating monocytes are a major source of tumor-associated macrophages (TAMs). TAMs in human breast cancer (BC) support primary tumor growth and metastasis. Neoadjuvant chemotherapy (NAC) is a commonly used treatment for BC patients. The absence of the response to NAC has major negative consequences for the patient: increase of tumor mass, delayed surgery, and unnecessary toxicity. We aimed to identify the effect of BC on the subpopulation content and transcriptome of circulating monocytes. We examined how monocyte phenotypes correlate with the response to NAC. The percentage of CD14-, CD16-, CD163-, and HLA-DR-expressing monocytes was quantified by flow cytometry for patients with T1-4N0-3M0 before NAC. The clinical efficacy of NAC was assessed by RECIST criteria of RECIST 1.1 and by the pathological complete response (pCR). The percentage of CD14+ and СD16+ monocytes did not differ between healthy women and BC patients and did not differ between NAC responders and non-responders. The percentage of CD163-expressing CD14lowCD16+ and CD14+CD16+ monocytes was increased in BC patients compared to healthy women (99.08% vs. 60.00%, p = 0.039, and 98.08% vs. 86.96%, p = 0.046, respectively). Quantitative immunohistology and confocal microscopy demonstrated that increased levels of CD163+ monocytes are recruited in the tumor after NAC. The percentage of CD14lowCD16+ in the total monocyte population positively correlated with the response to NAC assessed by pCR: 8.3% patients with pCR versus 2.5% without pCR (p = 0.018). Search for the specific monocyte surface markers correlating with NAC response evaluated by RECIST 1.1 revealed that patients with no response to NAC had a significantly lower amount of CD14lowCD16+HLA-DR+ cells compared to the patients with clinical response to NAC (55.12% vs. 84.62%, p = 0.005). NGS identified significant changes in the whole transcriptome of monocytes of BC patients. Regulators of inflammation and monocyte migration were upregulated, and genes responsible for the chromatin remodeling were suppressed in monocyte BC patients. In summary, our study demonstrated that presence of BC before distant metastasis is detectable, significantly effects on both monocyte phenotype and transcriptome. The most striking surface markers were CD163 for the presence of BC, and HLA-DR (CD14lowCD16+HLA-DR+) for the response to NAC.