Cancer immunotherapy has revolutionized the treatment landscape across malignancies; nevertheless, only a minority of our patients benefit. Moreover, we don’t fully understand the underlying mechanisms of response and resistance. Elucidating the molecular and cellular pathways that determine immunotherapeutic response and resistance can unlock novel biological and therapeutic insights.
High-dimensional tools offer an unparalleled look inside the tumor ecosystem and its inter- and intra-cellular circuitry. Our laboratory leverages multi-omic methods to deconvolute the cancer-immune interactions in the tumor microenvironment that drive patient outcome. We pair unbiased discovery approaches with ex-vivo and in vitro investigations that functionally confirm our hypotheses. Specifically, we define the molecular phenotypes and identities of heterogeneous cancer and immune populations that drive anti-leukemic immune responses. These data provide both biomarkers that predict immunotherapeutic response and nominate therapeutic targets whose modulation can reverse immunotherapeutic resistance.
We have demonstrated the critical role for autophagy in determining resistance to CTLA-4 blockade (Cell 2018); elucidated leukemic evolutionary trajectories shaping the graft-versus-leukemia (GvL) effect after bone marrow transplant (NEJM 2016; Sci Transl Med 2020; Blood 2021; Blood Adv 2021) and recently married single cell technologies with novel computational methodologies to predict and explain the role of exhausted T cell subsets in response to adoptive cellular therapy (Cell Reports 2021). Thus, human immunology [molecular and cellular] is critical to our approach.
Examples of projects in our laboratory include:
- defining the master regulators of intraleukemic T cell dysfunction;
- elucidating oncogene-driven immune suppression;
- decoding the spatial features of leukemia antigen-specific immunity within the microenvironment;
- identifying determinants of effective innate immune responses.
Please contact us if you share a similar passion!