Directing Traffic: How to Effectively Drive T Cells into Tumors

Abstract

Although immune checkpoint inhibitors (ICI) have demonstrated clinical activity in multiple tumor types, the majority of patients do not respond to ICI monotherapy. Mounting evidence suggests that ICI-mediated clinical responses rely upon tumor infiltration by T cells that are able to recognize and kill cancer cells. Here, we review therapeutic modalities that have been shown to promote T-cell infiltration into human tumors in studies to date, and discuss emerging data guiding how these modalities can be sequenced in order to optimize T-cell effector function and memory T-cell generation, while minimizing overactivation and potential toxicity. SIGNIFICANCE: The lack of preexisting T-cell inflammation in tumors is a major barrier to effective cancer immunity. A deep understanding of the mechanisms that prevent T cells from trafficking into the tumor in a given individual will be critical for tailoring immunotherapy combinations that can overcome resistance to ICI in patients with cancer.

Figure 1.. Tumor Immune Profiles

Three immune profiles of tumors – inflamed, immune-excluded, and immune-desert – correlate with responsiveness to checkpoint blockade. Features of each profile highlight therapeutic targets for reprogramming the microenvironment.

Figure 2.. Steps to drive tumor-specific T cells into tumors

(i) T cell priming, (ii) T cell expansion to achieve sufficient numbers, and (iii) trafficking and infiltration into tumor microenvironment

Figure 3.. Rational combination

Sequencing agents to promote T cell infiltration and optimal functionality