Andy J. Minn, M.D., Ph.D.
421 Curie Blvd
BRB II/III, Room 510
Philadelphia, PA 19104
The University of Chicago, Chicago, IL, 1992.
The University of Chicago, Chicago, IL, 1999.
The University of Chicago, Chicago, IL, 2000.
Description of Research ExpertiseKEYWORDS: Immune checkpoint blockade, interferon, pattern recognition receptors, anti-viral signaling, therapy resistance, exosomes, genomics, breast cancer, melanoma, radiation
A vast majority of human tumors express interferon-stimulated genes (ISGs), indicating that the activation of pathways controlling the induction of ISGs is a pervasive feature of cancer. Typically, ISGs result from pathogens, such as viruses, that are recognized by a class of receptors called pattern recognition receptors (PRRs). This leads to the induction of the anti-viral cytokine interferon (IFN). In the context of viral infection, this anti-viral response has many effects that include direct anti-pathogen function, regulation of innate and adaptive immune responses, and control of tissue regeneration. However, in the case of cancer, the engagement of PRRs and subsequent expression of ISGs is generally not due to virus infection but rather endogenous molecules in cancer cells and/or the tumor microenvironment that mimic viruses. A main focus of my research program is to understand: 1) the nature of the endogenous molecules in cancer cells or the tumor microenvironment that can mimic viruses, 2) why cancer cells evolve to recognize endogenous molecules as they would foreign pathogens, 3) what function this serves, and 4) the clinical/translational relevance of this "virus mimicry".
Emerging evidence indicates that in tumors, IFN and anti-viral signaling pathways can be activated by endogenous nucleic acids. This recognition of self RNA and/or DNA as foreign can occur during cancer progression or in response to cancer therapies. What ensues include a wide variety of different and often opposing effects on cancer cells and immune cells in the tumor. For example, one important consequence of IFN/PRR signaling in cancer is its impact on the immune system and on response to cancer immunotherapy. Activation of anti-viral pathways can engage the immune system against cancer to enhance efficacy of immune checkpoint blockade and chimeric antigen receptor (CAR) T cells. This is one rationale for combining conventional cancer therapies such as radiation and chemotherapy with immunotherapy. However, chronic PRR/IFN signaling can also have unwanted consequences. In particular, prolonged IFN signaling in the tumor that accompanies persistent disease can unexpectedly promote immunosuppression through IFN-mediated feedback inhibition. This inhibitory property of IFN signaling is a normal homeostatic function that is evident in chronic pathogen infections and serves to limit immune-mediated pathology. In cancer, tumors can co-opt this suppressive function of IFN signaling to render them particularly resistant to immunotherapy and to attack by adaptive and innate immune cells. Other unfavorable properties of IFN/PRR signaling in cancer include the promotion of tumor progression, metastasis, and even resistance to conventional cancer therapies.
To better understand the regulation, function, and significance of PRR/IFN signaling in cancer, cancer therapies, and immune regulation, we rely on multiple strategies. First, we utilize approaches that enable data-driven hypothesis generation using data acquired from biological systems that capture effects of cell-cell (particularly cancer and immune cell) interactions. This includes a reliance on in vivo and genome-based methods. Second, to understand disease-relevant biology, we prioritize perturbation effects that appear shared between mouse models and human cancer. Ultimately, our objective is to translate findings from bench to bedside by working with colleagues to inform the design of clinical trials.
Many rotation projects related to the research interests described are available. Please contact Dr. Minn to inquire.
Lex Johnson, Graduate student (Immunology)
Bihui Xu, Graduate student (Cancer Biology)
Erica Dhuey, Graduate student (Cancer Biology)
Lisa Cucolo, Graduate student (Cell Biology)
Jingya Qiu, Graduate student (Genomics and Computational Biology)
Darwin Ye, Graduate student (Cancer Biology)
Yuwei Qi, Graduate student (Cell Biology)
Shangshang Wang, Graduate student (Chemistry)
Yuanming Xu, Postdoc
Fevzi Demircioglu, Postdoc
Xiang Ni, Postdoc
Caitlin Foley, Research fellow
Yongjun Yu, Senior lab manager
Selected PublicationsJoseph L. Benci, Lexus R. Johnson, Ruth Choa, Yuanming Xu, Jingya Qiu, Zilu Zhou, Bihui Xu, Darwin Ye, Katherine L. Nathanson, Carl H. June, E. John Wherry, Nancy R. Zhang, Hemant Ishwaran, Matthew D. Hellmann, Jedd D. Wolchok, Taku Kambayashi, Andy J. Minn: Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade. Cell in press, 2019.
Patel Shetal A, Minn Andy J: Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies. Immunity 48(3): 417-433, Mar 2018.
Harding Shane M, Benci Joseph L, Irianto Jerome, Discher Dennis E, Minn Andy J, Greenberg Roger A: Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548(7668): 466-470, Aug 2017.
Benci Joseph L, Xu Bihui, Qiu Yu, Wu Tony J, Dada Hannah, Twyman-Saint Victor Christina, Cucolo Lisa, Lee David S M, Pauken Kristen E, Huang Alexander C, Gangadhar Tara C, Amaravadi Ravi K, Schuchter Lynn M, Feldman Michael D, Ishwaran Hemant, Vonderheide Robert H, Maity Amit, Wherry E John, Minn Andy J: Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell 167(6): 1540-1554.e12, Dec 2016.
Nabet Barzin Y, Qiu Yu, Shabason Jacob E, Wu Tony J, Yoon Taewon, Kim Brian C, Benci Joseph L, DeMichele Angela M, Tchou Julia, Marcotrigiano Joseph, Minn Andy J: Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer. Cell 170(2): 352-366.e13, Jul 2017.
Minn Andy J, Wherry E John: Combination Cancer Therapies with Immune Checkpoint Blockade: Convergence on Interferon Signaling. Cell 165(2): 272-5, Apr 2016.
Twyman-Saint Victor Christina, Rech Andrew J, Maity Amit, Rengan Ramesh, Pauken Kristen E, Stelekati Erietta, Benci Joseph L, Xu Bihui, Dada Hannah, Odorizzi Pamela M, Herati Ramin S, Mansfield Kathleen D, Patsch Dana, Amaravadi Ravi K, Schuchter Lynn M, Ishwaran Hemant, Mick Rosemarie, Pryma Daniel A, Xu Xiaowei, Feldman Michael D, Gangadhar Tara C, Hahn Stephen M, Wherry E John, Vonderheide Robert H, Minn Andy J: Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520(7547): 373-7, Apr 2015.
Boelens Mirjam C, Wu Tony J, Nabet Barzin Y, Xu Bihui, Qiu Yu, Yoon Taewon, Azzam Diana J, Twyman-Saint Victor Christina, Wiemann Brianne Z, Ishwaran Hemant, Ter Brugge Petra J, Jonkers Jos, Slingerland Joyce, Minn Andy J: Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159(3): 499-513, Oct 2014.
Jiang Yuchao, Qiu Yu, Minn Andy J, Zhang Nancy R: Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing. Proceedings of the National Academy of Sciences of the United States of America 113(37): E5528-37, Sep 2016.
Ishwaran Hemant, Kogalur Udaya B, Gorodeski Eiran Z, Minn Andy J, Lauer Michael S: High dimensional variable selection for survival data. Journal of the American Statistical Association 105: 205-17, Mar 2010.