Abstract B025: MHC class II and CD1d expressing conventional dendritic cells with immunoglobulin therapy drives anti-tumor abscopal effect by recruiting Natural Killer T cells to the tumor microenvironment
Authors: Garg Saurabh K , Snyder Colin , Ramamoorthi Ganesan , Evans Elizabeth E , Aldrich Amy L , Gautam Namrata , Wiener Doris , Lee Marie C , Han Hyo S , Gary Koski K , Czerniecki Brian J 
Published: February 2024

Abstract
Background Dendritic cells (DC) are the primary antigen presenting cells in the body responsible for processing and presenting MHC Class I and II antigens to initiate adaptive T cell response against cancer. In addition to MHC, DC also express non-classical receptors such as CD1d to activate invariant TCR α chain natural killer T (iNKT) cells. The conventional type-I dendritic cells (cDC1) presenting MHC class-II tumor associated antigens within tumor microenvironment (TME) have shown robust efficacy in mouse models of breast cancer (BC). Here, we have extended prior knowledge to deliver DC-based therapeutics, co-presenting class II antigens and CD1d directly to TME to show the potential of co-stimulation of multiple effector T cells in combination of tumor specific antibody (IgG1) mediating antibody dependent cellular cytotoxicity (ADCC). We hypothesize that merger of adaptive and innate responses will attain greater pathologic response in pre-clinical and clinical settings to design futuristic therapeutics against BC. Methods Present study uses variety of pre-clinical mouse models of BC and other types of cancer to test the therapeutic efficacy of intratumoral delivery of mouse bone marrow-derived conventional type I (CD103+ CD1d+) polarized DC pulsed with MHC class II HER2-derived peptides (HER2-DC1) in combination with systemic delivery of tumor specific IgG1 (aSEMA4D) to evoke ADCC. Cellular mechanism of response was evaluated using downstream methods including multiplex immunofluorescence, flow cytometry, and transcriptomics assays. Results We exhibit that specifically intratumoral combination therapy of HER2-DC1 expressing CD1d and aSEMA4D primes both innate and adaptive immune responses to completely regress tumor in 75-80% of mice with significant survival advantage in comparison to mice that received no therapy or monotherapies. The early CD4 Th1 response through interferon gamma combined with ADCC played a critical role in the decrease of pro-tumorigenic myeloid cells and increase in anti-tumor effector cells with a major contribution from classical CD4+ NKT cells within the TME. Interestingly, intratumoral combination therapy intensified DC1 migration from primary tumor to secondary tumor sites along with dynamic changes in subpopulations of DC with an associated increase in NKT cells at untreated tumor sites to display abscopal effect. Likewise, early data from phase I/II clinical trial illustrated great potential of cDC1 and IgG1 combination therapy to recruit anti-tumor effector cells such CD8 and NKT cells to mediate cancer eradication in HER2+ BC setting. Conclusions Specifically, intratumoral delivery of HER2-DC1 in combination with anti-tumor antibody mediating ADCC shows great promise for future BC clinical trials and improved patient outcomes. Furthermore, present study highlighted the role of NKT cells in favorable anti-tumor response. Our future studies are focused on understanding the crosstalk between DC and NKT to modulate the function of various cell types in TME to design improved cancer immunotherapies.
Citation Format: Saurabh K Garg, Colin Snyder, Ganesan Ramamoorthi, Elizabeth E Evans, Amy L Aldrich, Namrata Gautam, Doris Wiener, Marie C Lee, Hyo S Han, Koski K Gary, Brian J Czerniecki. MHC class II and CD1d expressing conventional dendritic cells with immunoglobulin therapy drives anti-tumor abscopal effect by recruiting Natural Killer T cells to the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B025.