Chemotherapy Induces Tumor-Associated Macrophages that Aid Adaptive Immune Responses in Ovarian Cancer

Abstract

Neoadjuvant chemotherapy (NACT) may stimulate anticancer adaptive immune responses in high-grade serous ovarian cancer (HGSOC), but little is known about effects on innate immunity. Using omental biopsies from HGSOC, and omental tumors from orthotopic mouse HGSOC models that replicate the human tumor microenvironment, we studied the impact of platinum-based NACT on tumor-associated macrophages (TAM). We found that chemotherapy reduces markers associated with alternative macrophage activation while increasing expression of proinflammatory pathways, with evidence of inflammasome activation. Further evidence of a shift in TAM functions came from macrophage depletion via CSF1R inhibitors (CSF1Ri) in the mouse models. Although macrophage depletion in established disease had no impact on tumor weight or survival, CSF1Ri treatment after chemotherapy significantly decreased disease-free and overall survival. This decrease in survival was accompanied by significant inhibition of adaptive immune response pathways in the tumors. We conclude that chemotherapy skews the TAM population in HSGOC toward an antitumor phenotype that may aid adaptive immune responses, and therapies that enhance or sustain this during remission may delay relapse.

Macrophages as tools and targets in cancer therapy

“…Cancer cells can disseminate via the serous cavities as is the case for ovarian cancer in the peritoneum. Macrophages contribute to secondary peritoneal implantation of cancer cells and can affect the response to chemotherapy and immunotherapy 4 , 62 , 274 . Perineural invasion is a forgotten pathway of cancer spreading occurring in different tumours and in particular in pancreatic ductal adenocarcinoma (PDAC) 275 .…”

“…Selected anticancer drugs can revert TAM polarization, resulting in increased response to the treatment such as gemcitabine in pancreatic cancer 61 , 5-fluorouracil in CRC 56 and platinum-based neoadjuvant chemotherapy in high-grade ovarian cancer 62 . For drugs that induce DNA damage via the generation of reactive oxygen species (ROS), such as platinum-based chemotherapies, the gut microbiome can prime intratumour mononuclear phagocytes to produce ROS, positively modulating the efficacy of these agents 39 , 63 .…”

“…In this context, macrophages act by contributing to the activation of adaptive immune responses by anticancer treatments 59 , 62 , by cooperating in tumour cell killing 56 , 61 and by being a target themselves 60 , 65 . In a seemingly opposite direction, TAMs limit the effectiveness of selected chemotherapeutic agents, driving detrimental reactive responses to tissue damage cues and rapidly reprogramming towards a pro-remodelling state 4 , 58 , 66 .…”

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

“…The peritoneal TME contains cancer cells, stromal cells, and immune cells, and the interactions between them influence tumor progression and immune escape and may represent specific targets for immunotherapy [ 15 ]. For example, chemotherapy skews the tumor associated macrophage (TAM) population in HSGOC toward an M1 antitumor phenotype (rather than protumor M2 phenotype) that aids adaptive immunity, and macrophage depletion via CSF1R inhibitors after chemotherapy treatment reduced adaptive antitumor immune responses and significantly decreased disease-free and overall survival in mice [ 16 ]. Therapies that enhance or sustain antitumor macrophages during chemotherapy-induced remission can potentially delay ovarian cancer relapse [ 16 ].…”

“…For example, chemotherapy skews the tumor associated macrophage (TAM) population in HSGOC toward an M1 antitumor phenotype (rather than protumor M2 phenotype) that aids adaptive immunity, and macrophage depletion via CSF1R inhibitors after chemotherapy treatment reduced adaptive antitumor immune responses and significantly decreased disease-free and overall survival in mice [ 16 ]. Therapies that enhance or sustain antitumor macrophages during chemotherapy-induced remission can potentially delay ovarian cancer relapse [ 16 ]. In a 2020 prospective observational study of ovarian cancer patients, there was a significant positive association between the M1/M2 ratio and an improved OS, PFS, and platinum-free interval (PFI), both in the entire population and in patients stratified according to tumor type and initial surgery [ 17 ].…”