"Engineering the Immune Response to 'Self' for Effective Cancer Immunotherapy"

Michelle Krogsgaard, PhD
Assistant Professor
Perlmutter Cancer Institute & Department of Pathology
New York University School of Medicine

Michelle Krogsgaard, Perlmutter Cancer Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016. T-cells play a critical role in host defense against viruses, intra- and extracellular microbes, and tumors. Because foreign antigen is presented amongst a vast majority of self-antigens, T-cells have evolved the unique ability to discriminate “self” from “non-self” with high sensitivity and selectivity, enabling the elimination of foreign pathogens while largely avoiding self-reactivity. However, tissue-specific autoimmunity and tolerance to or eradication of cancer does not fit neatly into the self/non-self paradigm because the T-cell responses in these situations are not directed to an exogenous pathogen, but rather most often to non-mutated self-proteins. Therefore, an important question is how the immune system establishes suitable thresholds that allow positively selected T-cells to interact with self-ligands in the periphery without causing overt activation. One hypothesis to explain how a T-cell distinguishes among different types of self-ligands is the kinetic proof-reading (KP) theory, which relates signaling efficacy to the life-time of the TCR-pMHC interaction. More recently, T-cell maturation associated signaling feedback pathways have also been hypothesized to play a role in T-cell discrimination of between self-ligands. We are taking a variety of biophysical and cellular imaging approaches to determine how specific thresholds for T-cell recognition of self-antigens are set. Our recent results indicate that antitumor activity and autoimmunity are coupled and have a similar kinetic threshold; reducing autoimmunity cannot be accomplished without sacrificing efficacy of tumor killing. Therefore, an “optimal TCR affinity range” that leads to optimal tumor regression and minimal autoimmunity is elusive and treatment strategies focusing on increasing TCR affinities to a supraphysiological level has most likely little therapeutic benefit. New strategies to overcome this issue includes engineering of TCRs and T-cell signaling pathways to carefully balance tumor-reactivity and autoimmunity. Supported by NIH, The American Cancer Society, The Pew Trust and The Cancer Research Institute.