Expression of tumour-specific antigens underlies cancer immunoediting.

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.

The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug Discovery.

Here, we explore the manipulation of immune cell metabolism as a strategy in target discovery and drug development for immune-mediated diseases. Comparing exploitation of metabolic pathways to kill tumor cells for cancer treatment with the reprogramming of immune cells to treat autoimmune diseases highlights differences that confer several advantages to the latter (including a more favorable therapeutic index and greater target stability). We discuss technological capabilities and gaps, including the challenge of relating in vitro observations to in vivo biology. Finally, we conclude by identifying future opportunities that will move the field forward and accelerate drug discovery.

The role of mutations in the cohesin complex in acute myeloid leukemia.

Mutations in the members of the cohesin complex have recently been identified as early events in acute myeloid leukemia (AML) pathogenesis. Studies conducted by our lab and others have shown that cohesin mutations or knockdown of cohesin subunits impair hematopoietic differentiation and enforce stem cell programs in both human and mouse hematopoiesis. Furthermore, studies in both models demonstrated global changes in chromatin accessibility and structure, in particular increased accessibility at binding sites for hematopoietic stem and progenitor cell (HSPC) transcription factors. These results suggest that mutations in the cohesin complex may contribute to leukemogenesis through modulation of HSPC chromatin accessibility. Future studies will be necessary to determine the detailed mechanisms mediating these phenotypes.

Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.

Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease.

Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression.

Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here, we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors.