RESUMO
Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient requiring the deployment of combination therapies for optimal efficacy. Here we thus explore mechanisms underlying sensitivity and resistance to PARPi using two intrinsically PARPi sensitive (T22) and resistant (T127) syngeneic murine breast cancer models in female mice. We demonstrate that tumor associated macrophages (TAM) potentially contribute to the differential sensitivity to PARPi. By single-cell RNA-sequencing, we identify a TAM_C3 cluster, expressing genes implicated in anti-inflammatory activity, that is enriched in PARPi resistant T127 tumors and markedly decreased by PARPi in T22 tumors. Rps19/C5aR1 signaling is selectively elevated in TAM_C3. C5aR1 inhibition or transferring C5aR1hi cells increases and decreases PARPi sensitivity, respectively. High C5aR1 levels in human breast cancers are associated with poor responses to immune checkpoint blockade. Thus, targeting C5aR1 may selectively deplete pro-tumoral macrophages and engender sensitivity to PARPi and potentially other therapies.
Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Inibidores de Poli(ADP-Ribose) Polimerases , Receptor da Anafilatoxina C5a , Macrófagos Associados a Tumor , Animais , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Camundongos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Humanos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/metabolismo , Receptor da Anafilatoxina C5a/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacosRESUMO
In this study, we compared the degree of oxidation of pork patties refrigerated at 7 °C for 0, 7, and 14 days and the content of 10 types of heterocyclic amines (HCAs) after heating. The pork patties used in the study were added with 0.7 mg sodium nitrite (SN) and 5 mg paprika extract (PE), respectively. IQx (2-Amino-3-methyl-imidazo[4,5-f]-quinoxaline), MeIQx (2-Amino-3, 8-dimethyl-imidazo[4,5-f]-quinoxaline), PhIP (2-Amino-1-methyl-6-phenyl-imidazo[4,5-b]-pyridine), and Harman (1-Methyl-9H-pyrido[4,3-b]-indole) contents increased with increasing storage periods of treatment. On the other hand, HCAs production in SN and PE treatments were suppressed over the storage period, with IQ (2-Amino-3-methyl-imidazo[4,5-f]-quinoline) and Aαc (2-Amino-9H-dipyrido[2,3-b]-indole) being suppressed significantly (P < 0.05). The control's pH, cooking loss, lipid, and protein oxidation were higher than SN and PE-treated patties at 14 d (P < 0.05). These differences affect the formation of HCAs. PLS-DA showed a strong correlation between protein oxidation and IQx, Harman, 4,8-DiMelQx (2-Amino-3, 4, 8-trimethyl-imidazo[4,5-f]-quinoxaline), PhIP, and MeIQx, while lipid oxidation correlated with IQx, Harman, and PhIP. Both SN and PE showed HCAs inhibitory activity and exhibited oxidative stability during storage.