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Project description:Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity. VIDEO ABSTRACT.
| S-EPMC8574993 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that a majority of patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers but impacts on breast cancer (BC) remain unknown. In obese mice fed an obesogenic or lean controls on a low fat diet, mice are injected with BC cells andtreated with anti-PD-1 or control. Obesity leads to immunosuppression systemically in tumor-free mice that is exacerbated in tumor-bearing mice. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. Anti PD-1 significantly reduces immunosuppressive cells and elevates anti-tumor immune cells. Lamb2, downregulated by anti-PD1, significantly predict patient survival. Last, we identify a microbial signature associated with anti-PD-1 efficacy. In sum, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity.
2021-05-08 | GSE174053 | GEO
Project description:Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that a majority of patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers but impacts on breast cancer (BC) remain unknown. In obese mice fed an obesogenic or lean controls on a low fat diet, mice are injected with BC cells andtreated with anti-PD-1 or control. Obesity leads to immunosuppression systemically in tumor-free mice that is exacerbated in tumor-bearing mice. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. Anti PD-1 significantly reduces immunosuppressive cells and elevates anti-tumor immune cells. Lamb2, downregulated by anti-PD1, significantly predict patient survival. Last, we identify a microbial signature associated with anti-PD-1 efficacy. In sum, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity.
2021-05-08 | GSE174044 | GEO
Project description:Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [tumor]
| PRJNA728069 | ENA
Project description:Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer
| PRJNA728064 | ENA
Project description:The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.
| S-EPMC7923299 | biostudies-literature
Project description:Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]
| PRJNA728059 | ENA
Project description:Despite the therapeutic success of immune checkpoint blockade (ICB) therapy against multiple tumors, many patients still do not benefit from ICB. In particular, high-grade brain tumors, such as glioblastoma multiforme (GBM), have a very low response rate to ICB, resulting in several failed clinical trials. This low response rate might be caused by a lack of understanding of the unique characteristics of brain immunity. To overcome this knowledge gap, macroscopic studies of brain immunity are needed. We use single cell RNA sequencing to analyze the immune landscape of the tumor microenvironment (TME) under anti-PD-1 antibody treatment in a murine GBM model. We observe that CD8 T cells show a mixed phenotype overall that includes reinvigoration and re-exhaustion states. Furthermore, we find that CCL5 induced by anti-PD-1 treatment might be related to an increase in the number of anti-inflammatory macrophages in the TME. Therefore, we hypothesize that CCL5-mediated recruitment of anti-inflammatory macrophages may be associated with re-exhaustion of CD8 T cells in the TME. We compare our observations in the murine GBM models with publicly available data from human patients with recurrent GBM. Our study provides critical information for the development of novel immunotherapies to overcome the limitations of anti-PD-1 therapy.
| S-EPMC9794569 | biostudies-literature
Project description:In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.
| S-EPMC9479603 | biostudies-literature
Project description:Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, we explored the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses, leading to lymphocytic infiltrates and antitumor effect in distant (nonvirally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4(+) and CD8(+) T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.
| S-EPMC4106918 | biostudies-literature