Chemokines that govern T cell activity in tumors.

Local regulation of T cell-mediated immunity to solid tumors occurs at multiple levels, including their recruitment from the bloodstream to the tumor microenvironment (TME), coordinated crosstalk with different subsets of antigen-presenting cells (APCs) controlling their local survival, proliferation, and effector differentiation, as well as their egress from tumors via lymphatics. At each level, chemokines play essential roles, for instance, by guiding directional T cell migration across blood and lymphatic endothelial barriers or by promoting their spatial proximity and direct physical interactions with APCs to enable functional crosstalk. In this article, we will review recent mechanistic insights into the chemokine axes that guide T cell functions in TMEs in light of the emerging functional state heterogeneity of CD8 effector T cells and our growing understanding of how regulatory T cells restrain antitumor activity.

Interruption of the intratumor CD8 T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy.

PD-1 blockade unleashes potent antitumor activity in CD8 T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients.

The aged tumor microenvironment limits T cell control of cancer.

The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8 T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8 T cell infiltration and function.

Dendritic cells as shepherds of T cell immunity in cancer.

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses.