Elucidating the networks of immune stromal connections by Perturbation of Immunity in Cancer - towards developing novel therapeutic strategies

Introduction

Immune cells monitor and eliminate cancer cells, and thus keep tumors in check along the lifespan of an organism. However, tumors have evolved various mechanisms to avoid immune surveillance. Therefore, understanding these mechanisms and interfering with them to facilitate immune cell eradication of tumor cells is the focus of many successful immunotherapies.

Limitations of Immunotherapy

The efficacy of immunotherapy is limited to only a small fraction of patients and only certain types of cancers. Therefore, it is crucial to understand the immune-tumor interactions to develop new treatments.

Tumor Evasion Mechanisms

Moreover, tumor evasion mechanisms interfere with such treatments, as compensatory programs ensue soon after therapeutic intervention. These compensatory programs are not limited to tumor cells, but also occur in the stromal compartment of the tumor microenvironment (TME), which provides indispensable support to the tumor, and is often overlooked as a potential target for intervention.

Research Objectives

Here we aim to gain a fundamental understanding of all cellular networks within the TME, to elucidate the roles and programs carried out by each cellular element participating in the complex, multilevel interactions that occur before therapeutic intervention and afterward.

Aim 1

Toward this goal, we will map the entire spectrum of immune and stromal cell interactions in the TME. We will identify:

• Negative- and positive-tumor-regulator dependent programs
• Primary and compensatory programs
• Unique and shared programs across pathogenic conditions
• Cell-intrinsic and extrinsic programs

Aim 2

Additionally, we aim to identify conserved mouse and human pathways using a parallel mouse and human tumor slice culture system.

Aim 3

Based on Aims 1 and 2, we will test and validate new candidates for targeted rational combination therapy in vivo.

Conclusion

Our findings will lay the foundations for a fundamental understanding of tumor immunity dynamics in the TME and create a paradigm shift in immunotherapy.