Ming Li

The pervasive influence of the immune system on human health and disease underscores the importance of a mechanistic understanding of immune regulation under pathophysiological conditions such as cancer. Cancer immunology research in my laboratory aims to decipher the cellular and molecular basis of tumor-elicited innate and adaptive immune responses and develop mechanism-based interventions to unlock the untapped potential of the immune system for cancer therapy.

Our work has been instrumental in unraveling novel cancer immunosurveillance programs mediated by distinct lineages of innate lymphocytes, innate-like T cells, and tumor-associated macrophages as well as uncovering crucial adaptive T cell regulation pathways in cancer.

Using murine genetic cancer models and patient tumor specimens, we were the first to report that cell transformation induces tissue-resident cytotoxic innate lymphocytes and innate-like T cells with critical cancer surveillance functions. We found that tumor-resident cytotoxic type 1 innate lymphoid cells (ILC1s) arise from a differentiation pathway distinct from conventional natural killer (NK) cells, while tumor-resident killer innate-like T cells (ILTCKs) are selected as a T cell lineage distinct from conventional cytotoxic T lymphocytes (CTLs).

We were also the first to report that tumor growth induces monocyte-derived tumor-associated macrophages (TAMs) supported by juxtacrine Notch signaling by cancer cells. We found that TAMs can be dietarily and genetically reprogrammed to engage the evolutionarily ancient cell quality control mechanism–cell competition–for innate tumor suppression. Moreover, we found that monocyte-derived TAMs function as antigen-presenting cells to regulate CTL activation and exhaustion in tumors.

We also found that tumor growth induces overly activated regulatory T (Treg) cells with their CTL suppressor function titratable along the PI3K-Akt-Foxo1 signaling pathway to overcome cancer immune tolerance without triggering autoimmunity, which was corroborated in a clinical trial with a PI3K inhibitor. Furthermore, we found that tumor growth co-opts transforming growth factor-beta (TGF-beta) signaling to inhibit T helper (Th) cell-mediated cancer immunity, to which we have developed a therapeutic program.

Collectively, these findings demonstrate discrete classes of tumor-elicited immunity and tolerance responses, which supports cancer immunology as a new discipline that transcends the classical “self versus non-self” doctrine, with the underlying molecular and cellular circuitries exploitable for cancer therapies.