Expression of tumor antigens, or peptides derived from mutated or aberrantly expressed proteins, is critical for T cell recognition and targeting of cancer cells. Tumors can simultaneously express multiple antigens that elicit responses from different T cell clones, yet little is known about how these cooccurring responses interact. Intuitively, one might think the responses would be additive or synergistic, yet our recent data suggests this is not the case. We find that antigen dominance hierarchies form in tumors where T cells specific to one “dominant” antigen saturate the response and suppress T cells responding to additional “subdominant” antigens. Current work in the lab is focused on understanding mechanisms underlying this T cell competition in tumors and identifying therapeutic approaches that can promote broader and more cooperative T cell responses against tumors.

As an approach, we utilize genetically engineered mouse models paired with novel genetic tools and single-cell analysis platforms, including flow cytometry, single-cell RNA-sequencing and multiplexed imaging, to deeply investigate T cell biology in lung cancer. Mechanistic studies and preclinical immunotherapy trials in mice are complemented with analysis of human samples to facilitate translation of our findings to the clinic.

Antigen expression patterns in regulating T cell competition in tumors

We previously showed that antigen dominance hierarchies form in lung tumors when multiple antigens are ubiquitously expressed across cancer cells. However, human tumors are generally more heterogenous than this; for example, antigens are frequently expressed in only a fraction of the tumor or are expressed at different times during tumor progression. In this project, we are generating genetic tools to model different antigen expression patterns across tumors to understand what patterns promote T cell competition versus, potentially, cooperation, normally and in response to immunotherapies.

Therapeutic vaccination to remodel antigen hierarchies

Cancer neoantigen vaccines have emerged as a promising therapeutic approach to reinvigorate T cell responses against tumors and are currently in clinical trials. In our lung cancer mouse model, we have observed that vaccination can substantially improve the magnitude of the T cell response and “break” antigen dominance, preferentially expanding T cells directed against subdominant antigens and improving tumor control. We are currently conducting preclinical trials in mice to investigate strategies to improve vaccine efficacy and explore rationale combinations with other immunotherapies.

T cell receptor binding affinity in regulating T cell phenotypes in tumors

T cell receptor (TCR) binding of antigens presented on major histocompatibility molecules (MHC) is necessary for T cell activation and directs T cell killing of tumor cells. In this project, we are exploring how the strength of TCR binding to antigen (i.e. affinity) regulates T cell phenotypes and function in tumors. We are particularly interested in how CD8 T cells with TCRs of different affinities interact with each other, within and across antigen specificities, both in the context of endogenous anti-tumor T cell responses and adoptive T cell therapies

Microenvironmental factors regulating T cell competition in tumors

The lung tumor microenviornment becomes increasingly immunosuppressive over the course of tumor development. We are interested in understanding what factors support initial productive T cell immunity that become lost or limiting over time and may fuel T cell competition. We are also interested in factors that are upregulated and may dominantly suppress full T cell activation and effector differentiation. We are using CRISPR/Cas9 modulation of gene expression and spatial and single-cell profiling of the tumor microenviornment to characterize the role of candidate factors and identify promising targets for therapeutic intervention.