Publications by authors named "Shravan Madireddi"
Article Synopsis
- Immune checkpoint inhibitors (ICIs) like atezolizumab are effective cancer treatments, but many patients still face therapeutic resistance.
- High levels of interleukin 6 (IL-6) correlate with a poor response to atezolizumab in advanced cancers, indicating a potential target for overcoming resistance.
- Combining PD-L1 blockade with IL-6 receptor inhibition shows promising results in preclinical studies by enhancing the effectiveness of anti-tumor immune responses, suggesting IL-6 signaling inhibitors could improve ICI therapies in cancer patients.
Article Synopsis
- Genome engineering of T lymphocytes can enhance our understanding of their roles in cancer immunity and lead to advanced T cell therapies.
- Current viral methods for creating CAR T cells have drawbacks, such as limited targeting and inefficient production.
- The new nonviral technique presented allows for precise gene edits in human T cells using plasmid DNA and Cas9-RNP, offering high efficiency and maintaining T cell functionality for research applications.
Article Synopsis
- Myeloid cells interact continuously with stromal cells and their surrounding matrix, and the study focused on the role of the collagen receptor LAIR1 in these processes.
- LAIR1 was found to be highly expressed in myeloid cells, particularly in non-classical monocytes, and was shown to bind to the stromal factor Colec12, influencing fundamental cellular pathways.
- Mice lacking LAIR1 displayed reduced monocyte populations and enhanced melanoma growth, indicating that LAIR1 is important for the health and functionality of myeloid cells, relevant for both normal physiological processes and disease outcomes.
Article Synopsis
- - The study explores the role of CD8+ tissue-resident memory T cells, specifically those marked by CD103 expression, in suppressing cancer progression and their potential as predictors of immunotherapy response.
- - Researchers analyzed data from 1,868 cancer patients undergoing treatment with atezolizumab and found evidence that CD103+ T cells are significantly upregulated in inflamed tumors, showcasing important characteristics related to their anti-cancer function.
- - The results indicate that tracking the presence of CD103+ CD8+ T cells in tumors can help predict which patients are likely to benefit from PD-1/PD-L1 blockade treatments, implying ongoing anti-tumor immune responses are crucial for effective therapy outcomes.
Article Synopsis
- Immunogenetic variation in humans plays a crucial role in research, clinical diagnosis, and therapies, focusing on two main loci: HLA and KIR.
- The traditional methods for classifying these loci require biological specimens and both lab and computational techniques.
- Recent advances in next-generation sequencing and new algorithms show over 97% accuracy for HLA typing and over 99% for KIR gene detection, showing promise for clinical and research applications.
Article Synopsis
- - Elevated levels of interleukin-8 (IL-8) in plasma and tumor tissues were linked to reduced effectiveness of the immune checkpoint drug atezolizumab in patients with metastatic urothelial carcinoma and renal cell carcinoma.
- - Patients with lower baseline IL-8 levels had better responses to atezolizumab and chemotherapy, while those who showed a decrease in IL-8 during treatment had improved overall survival with atezolizumab.
- - Research revealed that IL-8 is mostly produced by myeloid cells in the immune system, and high IL-8 levels can suppress the body's ability to present antigens, highlighting the need for therapies to counteract IL-8's effects for better treatment outcomes.
Article Synopsis
- Researchers investigated T cell behavior in cancer patients, focusing on how certain T cells interact with cancer immunotherapy targeting PD1 and PDL1.
- Using advanced single-cell sequencing, they found that specific T cell populations can expand within tumors and also in normal tissues around them, with the most successful anti-PDL1 treatment responses linked to these expanded T cell clones.
- Their analysis revealed that these effective T cells could also be traced in the blood, indicating a potential method for identifying patients who are likely to respond well to treatment and suggesting ongoing immune activity against the cancer.
Article Synopsis
- - The study highlights the therapeutic potential of monoclonal antibodies that activate members of the tumor necrosis factor receptor superfamily (TNFRSF), which are vital for immune regulation and cell growth.
- - A significant challenge in using these antibodies is their dependence on high-order clustering, which complicates their pharmacological activation and has hindered the development of approved drugs in this category.
- - The research introduces a tetravalent biepitopic targeting method, demonstrating that it enhances the effectiveness of antibodies like OX40 and DR5, making them more potent in stimulating T cell activation without needing additional signals, thus filling a critical gap in TNFRSF therapeutic applications.
Stimulation of several TNF receptor family proteins has been shown to dampen inflammatory disease in murine models through augmenting the number and/or activity of regulatory T cells (Tregs). We recently found that one molecule, 4-1BB, used binding to Galectin-9 to exert its immunosuppressive effects and drive expansion of CD8Foxp3 Tregs. We now show that ligation of another TNFR family molecule, DR3, which has previously been found to strongly expand CD4Foxp3 Tregs and suppress inflammation, also requires Galectin-9.
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- Biologics targeting TNF family receptors can be effective for treating immune diseases, with antibodies to 4-1BB (CD137) currently undergoing clinical trials for both cancer and autoimmune conditions.
- Recent research indicates that the action of agonist anti-4-1BB, which helps reduce autoimmune and allergic inflammation, relies heavily on Galectin-9 (Gal-9), a protein that binds directly to 4-1BB.
- Gal-9 enhances 4-1BB’s function by promoting its aggregation and signaling in various immune cells, and its interaction is also conserved in humans, suggesting potential for targeted clinical therapies involving 4-1BB and similar proteins.
Article Synopsis
- * The study discovered that the protein 4-1BB (CD137), alongside CD103, identifies the DCs in mesenteric lymph nodes with the highest RALDH levels and is important for maintaining RALDH expression in these cells.
- * Mice lacking 4-1BB showed reduced ability to generate iTreg when exposed to oral antigens, indicating that 4-1BB plays a significant role in controlling RALDH expression and enhancing the immune regulatory
Article Synopsis
- Tumors transform conventional CD4(+) T cells into regulatory T cells (iTreg), helping them escape the immune response, making it crucial to prevent this conversion for better cancer treatments.
- Researchers found that a new molecule, SA-4-1BBL, can stimulate CD4(+) and CD8(+) T effector (Teff) cells, making them resistant to the suppressive effects of iTreg cells, which helps improve tumor fighting.
- The study shows that signaling through 4-1BB not only prevents the conversion of naïve T cells into iTreg cells but also enhances the effectiveness of Teff cells, suggesting it's a promising target for cancer immunotherapy.
Article Synopsis
- The tumor necrosis factor (TNF) and its receptor families include about 50 proteins that can influence how cells function, especially in the immune system.
- These proteins are involved in important processes like cell survival, differentiation, and the production of inflammatory molecules.
- Recent research highlights the role of TNF signaling in autoimmune and inflammatory diseases and discusses how genetic variations in these proteins may affect disease risk, suggesting they could be targets for new therapies.
Article Synopsis
- Cervical cancer is a major cause of death among women globally, and existing HPV vaccines do not effectively treat the disease, highlighting the need for new therapeutic vaccines.
- The HPV E7 oncoprotein is a promising target for these vaccines, but its low antigenicity necessitates the use of strong adjuvants to boost effectiveness.
- Research showed that a new engineered adjuvant, SA-4-1BBL, in combination with an HPV-16 E7 vaccine significantly eliminated tumors in 70% of treated mice by enhancing immune responses, particularly involving NK cells, which are crucial for the therapy's success.
Article Synopsis
- Therapeutic subunit vaccines targeting tumor-associated antigens (TAAs) are promising for cancer treatment, but their effectiveness is limited by weak immunogenicity, necessitating strong adjuvants.
- Researchers developed a soluble form of the costimulatory ligand 4-1BBL, combined with streptavidin (SA-4-1BBL), which enhances immune responses by improving the uptake and presentation of TAAs to immune cells.
- In animal studies, vaccines using SA-4-1BBL showed significant therapeutic effects against specific cancers by boosting T-cell responses and altering the balance of immune cell populations in tumors, highlighting its potential as an innovative component in cancer immunotherapy.
Agonistic Abs to select costimulatory members of CD28 and TNFR family have shown efficacy in various preclinical cancer immunotherapeutic settings. However, the use of agonistic Abs is often associated with severe toxicity due to non-specific activation of lymphocytes. We hypothesized that natural costimulatory ligands may serve as more potent and safer alternative to agonistic Abs for immunotherapy.
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- - Therapeutic vaccines offer a promising approach to cancer treatment but face challenges due to tumors' immune evasion tactics, which threaten to undermine these therapies' effectiveness.
- - Successful cancer vaccines may need safe immunomodulators or adjuvants that can enhance tumor-specific immune responses and counteract the immune evasion mechanisms utilized by tumors.
- - The ProtEx technology developed by the laboratory allows for the quick creation of costimulatory ligands that can boost immune responses, both when attached to tumor cells and in soluble form, making it a valuable tool for improving cancer vaccines.
Targeting CD4+CD25+FoxP3+ regulatory T-cells for the augmentation of cancer immunotherapy.
Curr Opin Investig Drugs
December 2007
Article Synopsis
- CD4+CD25+FoxP3+ T-regulatory (Treg) cells help maintain self-tolerance in the immune system and are also involved in how the body tolerates foreign substances, like cancer cells.
- These Treg cells can be recruited by tumors to dampen the immune response, making cancer treatments less effective.
- Research is focused on modifying Treg cell functions as a potential cancer therapy, but success relies on understanding how these cells interact with tumors and suppress immune activity.