Navigating Pathways of Innate Immunity and Epigenetic Memory in Checkpoint Immunotherapy - My laboratory has been at the vanguard of the discovery of costimulatory molecules and checkpoint inhibitors and their role in cancer. The field of cancer immunotherapy has mainly focused on the impact of immune checkpoints (IC) and their blockade on the activation of tumor-associated T cells. Although antigen recognition is important, it is only one component of the process required for efficient induction of adaptive immunity. Work in our existing program revealed that the PD-1 receptor is expressed in hematopoietic stem and progenitor cells (HSPC) and recruits canonical PD-1: SHP-2 inhibitory axis to the GM-CSFRc, suppressing the phosphorylation of the transcription factors HOXA10 which regulates myeloid cell differentiation, and IRF8 which epigenetically instructs the differentiation of monocytes and dendritic cells. In mice with myeloid-specific ablation of PD-1: SHP- 2 axis, tumor myeloid cells had a gene expression program of enhanced differentiation, activation, phagocytosis, chemokine activity, IFN-I, IL-1 and IL-6, which are required for generation of TEFF and TMEM responses. Bone marrow monocytes from these tumor bearing mice displayed enhanced expression of IFN-I, IL-1 and IL-6, and activation of STING and NLRP3, and transferred protective anti-tumor immunity to naïve hosts. These findings support the novel hypothesis that, in the context of cancer, engagement of the PD-1:SHP-2 axis during HSPC differentiation imprints a program compromising key APC activities required to stimulate antigen-specific T cell responses, whereas its abrogation unleashes such APC functions. Understanding and recapitulating this process will be the goal of my future project. This knowledge might lead to the identification of new targets for personalized immunotherapy and new strategies to overcome barriers of immunotherapy. To achieve these, during the next seven years, I will focus on the following research directions to: A. Determine the impact of ICs on emergency myelopoiesis in the context of cancer. Emergency myelopoiesis and innate immunity are intimately linked. We will systematically investigate how cancer cues and immune checkpoints affect HSPC and their progeny. B. Uncover the effects of myeloid-specific IC targeting on APC activities. We will examine how myeloid-specific IC ablation affects the function of key pathways of innate immunity, including STING and NLRP3, and determine implications on T cell anti-tumor responses. C. Identify the role of ICs in trained immunity and epigenetic memory. We will identify epigenetic changes in HSPC and their progeny, and will search for epigenetic marks associated with response or resistance to cancer immunotherapy. We will perform CRISPR screens to identify novel mediators of long-lasting anti-tumor protection by myeloid cells. Ultimately, we will use Next-Generation humanized NSG (huNSG) mice to create an autologous PDX system for personalized immunotherapy based on patient-specific myeloid vulnerabilities. My vision is to, one day, translate these discoveries into standard care therapies for cancer patients.
