Abstract PL03-03: Taming the beast: Strategies to target the immune-suppressive macrophage to enhance cancer immune therapy

Abstract

Abstract Advances in basic, translational and clinical research have revealed the power of cancer immune therapy. Checkpoint inhibitors and adoptive T cell therapies are novel, FDA approved therapeutic strategies that promote recruitment to and activation of tumor-reactive cytotoxic T cells. While promising, these strategies are not effective in all cancer patients, and resistance to therapy often develops. Recent advances in the study of the tumor microenvironment have revealed that tumor-associated myeloid cells accumulate rapidly in tumors where they promote resistance to checkpoint inhibitor therapy and adoptive T cell therapy, inhibit immune responses to tumor cells, and stimulate tumor progression. The most abundant of these myeloid cells, macrophages, usually serve as a first line of defense against pathogenic insults to tissues. These innate immune cells mount pro-inflammatory responses to pathogens and repair damaged tissues. However, in tumors, macrophages (TAMs) accumulate rapidly and potently suppress anti-tumor immunity and promote tumor progression. Preclinical studies have identified crucial pathways that regulate the recruitment, polarization, transcription and metabolism of TAMs during tumor progression. We have found that an isoform of PI3Kinase, PI3Kgamma, controls these pathways by activating mTORC1-mediated transcriptional and metabolic pathways that suppress cytotoxic T cell recruitment and activation. Targeting PI3Kgamma and its downstream effectors inhibits immune suppressive polarization and promotes NFkappaB activation and pro-inflammatory transcription in macrophages, thereby recruiting CD8+ T cells and stimulating T cell activation and memory. Novel therapeutics targeting PI3Kgamma stimulate cytotoxic T cell activation and recruitment and synergize with checkpoint inhibitors and chemotherapy in preclinical studies. Clinical trials with PI3Kgamma inhibitors such as IPI-549 (Infinity Pharmaceuticals) are currently underway and offer the promise of improved cancer outcomes for many tumor types. Citation Format: Judith A. Varner. Taming the beast: Strategies to target the immune-suppressive macrophage to enhance cancer immune therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr PL03-03.