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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: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
Project description:In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of "classic" ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.
| S-EPMC8777268 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) therapy is a revolutionary approach to treat cancers, but still have limited clinical applications. Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment (TME) as one major obstacle. The TME, characterized by acidity, hypoxia and elevated ROS levels, exerts its detrimental effects on infiltrating anti-tumor immune cells. Here, we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles (termed as CAT@CaCO3 NPs) as the simple yet versatile multi-modulator for TME remodeling. CaCO3 NPs can consume protons in the acidic TME to normalize the TME pH. CAT catalyzed the decomposition of ROS and thus generated O2. The released Ca2+ led to Ca2+ overload in the tumor cells which then triggered the release of damage-associated molecular patterns (DAMP) signals to initiate anti-tumor immune responses, including tumor antigen presentation by dendritic cells. Meanwhile, CAT@CaCO3 NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype, further enhancing tumor antigen presentation. Consequently, T cell-mediated anti-tumor responses were activated, the efficacy of which was further boosted by aPD-1 immune checkpoint blockade. Our study demonstrated that local treatment of CAT@CaCO3 NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses, inhibiting the growth of treated tumors and distant diseases.
| S-EPMC10660011 | biostudies-literature