Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Abstract

Epithelial ovarian cancer (EOC) is among the top five causes of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant cells to the peritoneum. Despite improvements in medical therapies, particularly with the implementation of novel drugs targeting homologous recombination deficiency, the survival rates of patients with EOC remain low. Unlike other neoplasms, EOC remains relatively insensitive to immune checkpoint inhibitors, which is correlated with a tumor microenvironment (TME) characterized by poor infiltration by immune cells and active immunosuppression dominated by immune components with tumor-promoting properties, especially tumor-associated macrophages (TAMs). In recent years, TAMs have attracted interest as potential therapeutic targets by seeking to reverse the immunosuppression in the TME and enhance the clinical efficacy of immunotherapy. Here, we review the key biological features of TAMs that affect tumor progression and their relevance as potential targets for treating EOC. We especially focus on the therapies that might modulate the recruitment, polarization, survival, and functional properties of TAMs in the TME of EOC that can be harnessed to develop superior combinatorial regimens with immunotherapy for the clinical care of patients with EOC.

Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination immunotherapy

“…VEGFA and VEGFB expressed in tumor cells potentially interact with NRP1 , and FLT1 is particularly expressed in endothelial cells. Blocking macrophage colony-stimulating factor CSF1 and its receptor CSF1R axis and several drugs that target these factors have been under investigation [71].…”

Identifying ITGB2 as a Potential Prognostic Biomarker in Ovarian Cancer

“…M2 macrophages commonly predominate in the ovarian cancer environment [ 22 , 23 ]. Thus, it may be crucial to reprogram the TAMs in TME to improve the strong immunosuppression and increase therapeutic effectiveness of ovarian cancer, with the aim of providing a new insight for immunotherapy in ovarian cancer [ 24 , 25 ]. Interestingly, based on the assessments of the TIMER and EPIC databases, we found that the tumor environment comprised CAFs (cancer-associated fibroblasts), CD4+/CD8+ T cells, and macrophages, revealing that the immune microenvironment of ovarian cancer presents a dichotomy between immune activation and suppression.…”

Mini‐review: Immunology in ovarian cancer

“…46,47 CCL2/CCR2 or CSF1/CSF1R blockades deplete TAMs and have been tested in clinical trials. [48][49][50] In addition, MDSCs are depleted by chemotherapies, such as anti-VEGF antibody, 5-fluorouracil, gemcitabine, or the CXCR2 blockade. 40,51,52 Immunotherapies should also aim to increase the number of neoantigens to allow T cells to target tumor cells.…”

“…Anti‐CLTA‐4, anti‐CD25, or anti‐CCR4 antibodies are good treatment options for Treg depletion 46,47 . CCL2/CCR2 or CSF1/CSF1R blockades deplete TAMs and have been tested in clinical trials 48–50 . In addition, MDSCs are depleted by chemotherapies, such as anti‐VEGF antibody, 5‐fluorouracil, gemcitabine, or the CXCR2 blockade 40,51,52 …”