Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment

Abstract

Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically evident nonetheless implies that immune escape must occur. Two major subsets of human melanoma metastases have been identified based on gene expression profiling. One subgroup has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and has been designated as non-T cell-inflamed. The mechanisms of immune escape are likely distinct in these two phenotypes, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, FoxP3⁺ Tregs, and evidence for T cell-intrinsic anergy. Therapeutic strategies to overcome these inhibitory mechanisms are being pursued, and anti-PD-1 mAbs have been FDA approved. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous, several of which are in clinical testing. A new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8α⁺ DCs. New strategies are being developed to engage this pathway therapeutically, such as through STING agonists. The molecular mechanisms that mediate the presence or absence of the T cell-inflamed tumor microenvironment are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway, suggesting that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment.

Keywords: Cancer immunotherapy; Checkpoint blockade; Dendritic cells; Immune evasion; Innate immune sensing; T cell dysfunction; T cell inflammation; Tumor microenvironment.

Fig. 2.1

Immunologic composition of the T cell-inflamed versus non-T cell-inflamed tumor microenvironments. The T cell-inflamed tumors contain variable numbers of CD8⁺ T cells and CD8α/CD103-lineage DCs, but also possess the highest density of FoxP3⁺ Tregs. In addition, many of the conventional T cells have a dysfunctional anergic phenotype. In contrast, the non-T cell-inflamed tumors lack these elements but still contain blood vessels, fibroblasts, and macrophages that help support tumor growth. Recruitment of CD8⁺ effector cells is largely dependent on the chemokines CXCL9 and CXCL10, which engage the receptor CXCR3. Treg recruitment is primarily driven by CCL22, which is in part produced by activated CD8⁺ T cells

Fig. 2.2

Immunotherapeutic targets that are preferentially relevant for the T cell-inflamed tumor microenvironment subset. T cell-inflamed tumors contain activated CD8⁺ T cells but also express IDO and PD-L1, which inhibit T cell function. The dysfunctional/anergic T cells in the tumor microenvironment also can express an array of additional inhibitory receptors, including LAG-3, Tigit, Tim3, and 2B4. But in addition, these T cells also para-doxically express costimulatory receptors, including 4–1BB, Ox40, ICOS, GITR, and CD27. Both blockade of inhibitory receptors and ligation of costimulatory receptors are being developed as cancer therapeutics. Additional candidate immune suppressive factors not shown here that have yet to be effectively targeted clinically include TGF-β, IL-10, iNOS, and PGE₂

Fig. 2.3

Summary of four types of strategies that could be considered to overcome the barrier of the non-T cell-inflamed tumor microenvironment. It is envisioned that intratumoral administration of innate immune activators or local tumor radiation, modulators of host polymorphic gene products, blockade of immune-exclusionary oncogene pathways, and delivery of probiotics that amplify anti-tumor immunity all could be considered for ultimate clinical translation