tumor antigens; cancer immunotherapy; lung cancer; T cell exhaustion
Thommen D.S., Koelzer V.H., Herzig P., Roller A., Trefny M., Dimeloe S., Kiialainen A., Hanhart J., Schill C., Hess C., Savic Prince S., Wiese M., Lardinois D., Ho P.C., Klein C., Karanikas V., Mertz K.D., Schumacher T.N., Zippelius A. (2018), A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade, in Nature Medicine
Koelzer V.H., Gisler A., Hanhart J.C., Griss J., Wagner S.N., Willi N., Cathomas G., Sachs M., Kempf W., Thommen D.S., Mertz K.D. (2018), Digital image analysis improves precision of programmed death ligand 1 (PD-L1) scoring in cutaneous melanoma, in Histopathology
Thommen D.S., Schumacher T.N. (2018), T Cell Dysfunction in Cancer, in Cancer Cell
, (33), 547-562.
Tumor-infiltrating T cells can recognize antigens that are presented on tumor cells and thereby mediate cancer regression. The successful elimination of tumor cells, however, is limited by the dysfunctionality of intratumoral T cells that are characterized by the expression of inhibitory receptors (also referred to as immune checkpoints) such as PD-1. Cancer immunotherapy targeting immune checkpoints has shown major successes in multiple cancer types during the last years and is now considered one of the pillars of cancer therapy. Furthermore, recent data suggest that mutational load and expression of ‘neo-antigens’ - T cell epitopes that arise as a consequence of tumor-specific mutations - may influence the response to cancer immunotherapy. Consistent with this, smoking-associated lung cancer, in which mutational loads are particularly high, has proven more susceptible to PD-1 blockade compared with lung cancer in non-smokers and therefore represents a highly interesting model to study both antigen specificity and dysfunction of intratumoral T cells. In spite of the major recent success in cancer immunotherapy, the number of long-term survivors still remains limited and many patients do not respond or relapse after immunotherapy, sometimes at the cost of severe toxicities. Crucially, while it is now broadly appreciated that T cells that are reactive towards cancer regression antigens represent a highly interesting therapeutic target, little is known about the (dys)functional state of these cells and their response to cancer immunotherapy. In this proposal we will determine the antigen specificity and kinship of intratumoral T cells with different degrees of dysfunction, thereby providing better insight into how to reactivate this T cell pool. Specifically, we showed previously that PD-1hi T cells express a profoundly exhausted phenotype with functional impairment and poor response to PD-1 blockade, in contrast to T cells expressing PD-1 at an intermediate level. It is currently unknown to which antigens these (highly) dysfunctional T cells are reactive and whether they represent two distinct T cell subsets that develop independently. To address this issue, we will characterize intratumoral T cell populations defined by the expression level of PD-1 in patients with non-small cell lung cancer using state-of-the-art technologies developed by the host lab. In a first step, we will perform a comprehensive functional and phenotypical characterization of distinct PD-1 subsets with the aim to identify potential markers that co-define these populations. In a second step, TCR repertoire analysis will be used to determine whether these T cell subpopulations are derived from the same T cell clones or develop independently. In the final part, the type and breadth of antigens that are recognized by T cells with distinct level of PD-1 expression will be investigated in lung cancer patients. In case our research shows that highly dysfunctional T cell subsets commonly recognize the neo-antigens that are considered of major importance for cancer regression, reactivation of these cells may be key to the further development of immunotherapeutic treatments. In addition, it would provide a rationale for the development of personalized cancer therapies such as combinations of checkpoint inhibitors and tumor vaccines or adoptive T cell therapy.