The effect of aging on cDC1 function and CD8 T cell immunity in tumors

Massachusetts General Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ ABSTRACT Aging is a well-established risk factor for the development of cancer and is associated with a gradual decline in immune function. Studies have indicated that this age-related decline in immune function can hamper the effectiveness of CD8+ T cell immunity and restrict the response to immunotherapy in older cancer patients, such as those with melanoma; however, the mechanism remains unclear. In order to gain a better understanding of this mechanism, I conducted experiments using melanoma tumor-bearing mice at different ages. The results revealed a decrease in conventional type 1 dendritic cells (cDC1s) within aged tumors and tumor-draining lymph nodes. These aged cDC1s exhibited defects in antigen presentation and failed to produce essential immunostimulatory molecules (e.g., Flt3, CXCL9, CXCL10). Previous research has emphasized the crucial role of cDC1s in maintaining and guiding the differentiation of progenitor-exhausted T cells (TProg or PD-1+TCF-1+ stem-like cells). These cDC1s play a key role not only by secreting critical chemokines, which are essential for enriching TProg cells in immune hubs, but also by facilitating antigen presentation to regulate the differentiation of TProg cells into potent effectors. Indeed, in my preliminary data, I observed the limited function and quantity of cDC1s in the aged tumor microenvironment (TME) as well as decreased effector cytokine production and proliferation capacity of TProg cells. Building on these findings, I propose to delve into the mechanisms underlying the defective function of cDC1s in the aged TME and how this limitation impacts the control of cancer by CD8+ T cells, with my mentors, advisor team, and collaboration. I hypothesize that aged intratumoral cDC1s with impaired function are unable to effectively shepherd TProg cell immunity, and rejuvenating aged cDC1 will be crucial for enhancing CD8+ T cell control of aged tumors. To test it, I will investigate how aged cDC1s influence TProg cell fate, including monitoring TProg lineage differentiation and exploring interventions to rejuvenate cDC1 function (Aim 1 – K99 phase). Independently, I will examine how aged cDC1s affect the organization of immune hubs. The objective is to characterize the immune hubs in young versus aged TME, evaluate changes in cDC1 localization and cDC1-CD8+ T cell crosstalk, assess how their crosstalk impacts TProg cell functions, and validate findings using melanoma patient tumor biopsies by using a spatial transcriptomics platform - Xenium (Aim 2 – K99/R00 phase). Furthermore, I will assess cDC1 development and persistence in aged hosts and explore therapeutic approaches. This involves examining systemic or local defects in cDC1 development by investigating cDC1 precursors across multiple organs, assessing cDC1 persistence in the aged TME, and evaluating myeloid- targeted approaches to enhance cDC1 number and functions (Aim 3 – R00 phase). By achieving these aims, I will provide a comprehensive understanding of cDC1-CD8+ T cell crosstalk mechanisms in the aged TME. This research will also offer a framework to enhance the functions of aged cDC1s and explore potential myeloid- targeted approaches for older melanoma patients.