Development of multiomic approaches and pipelines to discovery of biomarkers and elucidation of immune mechanisms related to treatment outcome in cancer patients

Abstract

The role of the immune response in response to conventional cancer therapy and disease progression or recurrence has been well established for many cancers. The era of checkpoint inhibitors (anti-PD1, anti-CTLA-4, anti-PD-L1, and others) has ushered in novel therapies that aim to activate a previously inhibited anti-cancer T cell response by blocking inhibitory receptor engagement. While checkpoint inhibitors have proven an important new approach to cancer treatment, winning the Nobel Prize in 2018, it is critical to understand the molecular and cellular mechanisms behind treatment failure and develop novel therapeutic options for use as standalone immunotherapies or as combination therapies with existing CPIs, cellular or standard chemo therapies. Many studies demonstrated unequivocal importance of inflammatory immune TME for control of cancer and response to therapy. Many cell subpopulations work together to create an activating or inhibitory TME and eventually influence the growth of a tumor and response to therapy or disease recurrence. These include several T cell subsets that are involved in a patient's anti-cancer response and broadly include CD4+ T cells, CD8+ T cells, and non-classical T cell subsets such as Double Negative (CD4-CD8- T cells) and NKT cells. While these T cell populations can have the potential to respond, several mechanisms of T cell tolerance/suppression can inhibit their activity and lead to an ineffective anti-cancer response. In addition to determining a given T cell's functional potential (Th1, Th2, Th17, Treg, cytolytic, etc.) and activation state (recently activated, chronically activated, anergic, and terminally or temporarily exhausted), it is critical to determine the dynamics of the T cell response as indicated by the structure of the T cell receptor (TCR). Studies of the TCR have been critical tools for understanding T cell biology and immunoregulation for over two decades, and particularly, early studies performed by myself using TCR Vbeta regions were key in demonstrating important aspects of T cell tolerance and anergy. The TME is clearly important for control of the antitumor response and response to therapy (both conventional and immunotherapy checkpoint inhibitors), however, the systemic immune response as measured in the circulating blood is also critical to investigate for a number of reasons. First, the peripheral blood often reflects an immune activation or inhibition that is taking place at specific local sites. Second, given the relatively easy availability of blood samples, we can perform longitudinal studies and correlate the peripheral immune response with the local TME and clinical outcomes (survival, disease recurrence, etc.). Third, companion biomarkers identified in the peripheral blood can be used for disease monitoring, identification of response to therapy or as prognostic markers, even if the immune profile is not specifically indicative of the TME activity. Thus, elucidation of these complex T cell and APC subpopulation interactions at both the tumor site (TME) and systemically, in cancer patients is a critical step in determining potential immunomodulatory targets that can contributing to response failure or success. (AU)