APC subsets and B7 family checkpoints in the human tumor microenvironment
APCs are a heterogeneous group of immune cells. The Zou laboratory has phenotypically and functionally studied different subsets of APCs including myeloid DCs, plasmacytoid DCs, macrophages, and MDSCs in the human tumor environment. They are the first research team to demonstrate that human cancer environmental and draining lymph node APCs highly express inhibitory B7-H1 (PD-L1) and B7-H4 (B7s, B7x), and blockade of these checkpoints enhances tumor specific T cell anti-tumor immunity. The laboratory has published a series of research articles, dating as early as 2003, on these checkpoint studies in patients with cancer. These human studies have laid the foundation for current clinical application of checkpoint blockade and have changed the view of tumor immunotherapy.
T cell subsets in the human tumor microenvironment
Tregs: The laboratory has demonstrated the phenotype, function, trafficking, metabolism, and clinical relevance of Tregs in human cancer In addition to FOXP3+ Tregs, they have defined an IL-10+CD8+ Treg population in human cancer, and plasmacytoid DCs induce the CD8+ Tregs. These studies demonstrate that Tregs are an important component of the immune suppressive networks in the human tumor microenvironment and effectively targeting Treg biology may be therapeutically meaningful.
Th17 cells: The laboratory has defined the phenotype, differentiation, regulation, functional, and clinical significance of Th17 cells in human cancer. They are one of the first research groups to determine that IL-2 and IL-1 play opposite roles in IL-17+ T cell differentiation and Th17 cells are highly plastic with polyfunctional and stem-like features, which are controlled by HIF-1a and Bcl-2 signaling pathway. This body of work has stimulated sizable interest and discussion in the field of Th17 cell basic biology and translation.
Th22 cells: The laboratory has studied Th22 cells and their role in the human colon cancer microenvironment.
CD8+ T cells: The laboratory has focused on exploring the metabolic mechanisms by which stem-like features and polyfunctionality of memory T cell subsets and naïve T cell phenotype are controlled in the human cancer microenvironment. They have found that human cancer imposes glucose restriction on memory and naive T cells and dampens their function. This data has unveiled a novel metabolic target and mechanism of cancer immune evasion and may provide a way to therapeutically target T cells for cancer therapy.
Cancer immune phenotype and immunotherapy response mechanisms
Cancer immunotherapy has demonstrated therapeutic responses. Yet, objective responses have been manifested in only a fraction of patients. The cellular and molecular mechanisms of immunotherapy response and non-response are the central questions to be addressed in the field. Th1-type chemokines CXCL9 and CXCL10 and effector T cell tumor infiltration are associated with cancer patient survival and are correlated with clinical response to PD-L1 and PD-1 blockade in some types of cancer. However, a crucial question is why some tumors are “inflamed” (hot) with effector T cell infiltration while others are “non-inflamed” (cold). The laboratory has hypothesized that immune protective Th1-type chemokines might be epigenetically regulated in cancer and in turn affect T cell tumor trafficking, cancer progression and clinical responses to immunotherapy. In collaboration with Dr. Arul Chinnaiyan’s laboratory, they have found that PRC2 and SWI/SNF complexes and DNMTs affect Th1-type chemokines and IFN-signaling pathway and abrogate cancer immunity mediated by PD-L1 blockade and adoptive T cell therapy. The data has shown that reprogramming epigenetic pathways will synergize current cancer immunotherapy. Thus, this research has revealed a mechanism that addresses the “inflamed” (hot) vs “non-inflamed” (cold) question and provided scientific rationale for a novel combinational regimen of epigenetic therapy and immunotherapy in patients with cancer.
Molecular mechanisms of immune cell subset trafficking into the human cancer microenvironment
The laboratory has defined the molecular mechanisms by which plasmacytoid DCs, Treg, Th22, and effector T cells traffic into the human tumor microenvironment. Chemokines and chemokine receptors including CXCL12/CXCR4, CCL22/CCR4, CCR6/CCL20, and CXCL9, CXCL10/CXCR3 play crucial roles in directing different immune cell subsets in tumor and bone marrow migration. The data suggest that manipulation of immune cell tumor trafficking may be an option for cancer immunotherapy.
Impact of immune elements on tumorigenesis, chemotherapy, and radiation therapy resistance in human cancer
The diversity of cancer is generated through genetic alterations as well as by epigenetic events regulated by the tumor microenvironment. Cellular interactions within the tumor microenvironment regulate both the cancer stem-like cell and bulk cell components which play an important role in tumor progression and metastasis. The laboratory has demonstrated that different immune components including inflammatory Tregs, Th22 cells, MDSCs, and macrophages are involved in the control of cancer stemness and angiogenesis. In collaboration with Dr. Max Wicha’s laboratory, they have dissected specific epigenetic pathways including microRNAs and histone modifications in the control of the interaction between immune cells and tumor (stem) cells. This body of work has generated cellular and molecular insights into the mechanistic relationship between “inflammation” and cancer and has demonstrated a non-immunological role for specific immune components in shaping cancer biology and therapy. On this basis, they have proposed the novel concept that cancer is not only a genetic disease, but also an immune disorder and a stem cell malady. This concept is an important complementation and revision on Knudson hypothesis of cancer causation and has important application in cancer therapy. The laboratory currently focuses on adaptive and innate immune mechanisms of chemotherapy and radiation therapy resistance. They have found that CD8+ T cells control system xc- cystine and glutamate antiporter, and abolish cancer cisplatin resistance in ovarian cancer. Furthermore, in collaboration with Dr. Fang’s team, they have shown that F. nucleatum targeted TLR4 and MYD88 innate immune signaling to control cancer chemoresistance in patients with colon cancer. In collaboration with Dr. Lawrence’s laboratory, they are exploring the impact of innate and adaptive immune pathways on radiation therapy. Their work suggests that capitalizing upon the interplay between chemotherapy/radiation therapy and immunotherapy holds promising potential for the treatment of patients with cancer.