Joseph Palmeri, PhD, CRI Lloyd J. Old Fellow Memorial Sloan Kettering Cancer Center Tumor-reactive CD8 T cells found in cancer patients are frequently dysfunctional, unable to halt tumor growth. While direct cytotoxic activity against cancer cells generally resides within the CD8 T cell compartment, various modes of action have been described for CD4 T cells in anti-tumor immunity. The Schietinger-lab recently investigated if and how tumor-specific CD4 T cells can be enlisted to overcome CD8 T cell dysfunction within tumors. Functional studies in tumor-specific CD8 and CD4 T cells, and dendritic cells (DC), revealed that the spatial positioning and interactions of CD8 and CD4 T cells dictate the anti-tumor response–not their numbers. The study found CD4 T cells must engage with CD8 T cells on the same DC during the effector phase within tumors, forming a three-cell cluster (triad) to license CD8 T cell cytotoxicity and CD8 T cell-mediated cancer cell elimination. When this triad formation was disrupted, tumors progressed. Strikingly, in mesothelioma patients treated with immune checkpoint inhibitors, only the formation of CD4 T cell::DC::CD8 T cell triads were associated with clinical responses, while CD4::DC dyads or overall numbers of CD8 or CD4 T cells did not affect the patient outcome. Thus, intratumoral triads are a key requirement for antitumor immunity and describe a new role for CD4 T cells. Dr. Joseph Palmeri completed his PhD from the Massachusetts Institute of Technology (MIT) and joined the Schietinger lab in September 2023 as postdoctoral fellow. Intrigued by the effect of immune triad in anti-tumor immune responses, Dr. Palmeri decided to focus his research on understanding the underlying mechanism(s) by which CD4 T cells and triads license cytotoxic CD8 T cells in tumors, and how to develop strategies and engineer therapeutics to promote triad formation within the tumor microenvironment as novel immunotherapeutic interventions. He is using novel cancer mouse models, vaccine therapeutics, as well as bi-and-trispecific cell-cell engagers to build a research program focused on both elucidating mechanism and designing therapeutics for triad-mediated destruction of tumors. Projects and Grants Intratumoral immune triads: Elucidating mechanisms and engineering novel therapeutics to promote anti-tumor immunity Memorial Sloan Kettering Cancer Center | All Cancers | 2024 | Andrea Schietinger, PhD
