CD4 T cells and immune cell triads in anti-tumor immunity

About This Grant

PROJECT SUMMARY CD8 T cells are powerful adaptive immune cells that have the ability to eradicate cancer cells. However, despite the presence of tumor-specific CD8 T cells (CD8 TST) tumors progress, suggesting that CD8 T cells become dysfunctional. While direct cytotoxic activity against cancer cells generally resides within the CD8 T cell compartment, CD4 T cells play important roles in priming and activation of naïve CD8 T cells in lymphoid tissues and enhancing CD8 T cell mobilization into peripheral tissues, including tumors. We recently investigated if and how tumor-specific CD4 T cells (CD4 TST) could be enlisted to overcome CD8 TST dysfunction/exhaustion in tumors (Espinosa et al., (2024)). Employing preclinical cancer models as well as human samples, we discovered that CD4 TST are critical during the effector phase within tumors: CD4 TST must co-engage with CD8 TST on the same dendritic cell (DC), forming a three-cell-cluster (triad) to license CD8 TST cytotoxicity and tumor destruction. Triad formation reprograms CD8 TST, preventing and even reversing CD8 TST dysfunction/exhaustion, ultimately leading to the elimination of large established tumors and long-term protection from recurrence. We showed that when triad formation is prevented in settings of immunotherapies, tumors progress even when equal numbers of CD8 and CD4 TST are present within tumors. Strikingly, we found that the presence of triads in tumors of patients treated with immune checkpoint blockade was associated with clinical responses. Thus, the unique spatial positioning and cell-cell interactions of CD4 T cells, CD8 T cells, and DC are critical for anti-tumor responses. These intriguing findings have now led us to ask how CD4 TST in immune cell triads license CD8 TST to kill cancer cells. Which transcription factors (TF) and polarization state(s) are required for CD4 TST effector function within triads? Which receptor/ligand and/or cytokine/chemokine signals mediate CD8 TST cytotoxicity? Which signals do DC provide to CD4 TST and/or CD8 TST? Are specialized DC subsets, phenotypes, or maturation states needed? In this application, we will leverage the power of preclinical cancer models and unique human samples, employ state-of-the-art technologies, and design and test innovative strategies to identify the critical molecular factors and signals within triads and test how they can be enforced for the treatment of cancer. This work will provide mechanistic insights into the immune cell interactions critical for tumor control and inform strategies to enhance immunotherapy responses.