macrophage - CASANOVA ACEBES LAB

Immune checkpoint blockade (ICB) has revolutionized cancer care yet is ineffective in most patients. Predicting which patients will respond to ICB and how to enhance efficacy are major challenges. ICB efficacy is dependent on the presence of functional T cells in tumors, which are impacted by macrophages. We have discovered that lipid-laden macrophages (LLM) infiltrate ovarian tumors to promote cancer progression in association with immune evasion (Nat. Comm 2018). How LLMs accumulate lipids to impact ICB and whether they are predictive of ICB efficacy remain unexplored. Our objective is to determine how LLMs limit ICB and how this can be controlled via diet modulation. We hypothesize that LLM predict poor ICB response and that targeting LLM will enhance ICB efficacy. Our goals are to determine (i) the utility of LLM in predicting ICB efficacy and T cell dysfunction in patients; (ii) the origin and functional role of LLM in immunosuppression, hematopoiesis and ICB resistance; & (iii) how LLM and ICB are impacted by diet and obesity. We focus on tumors near lipid-rich adipose tissue, such as ovarian cancer (OC) which have high LLM and respond poorly to ICB.

Cancer can progress rapidly and every minute lost in ineffective treatment increases the likelihood that the patient will die. Therefore, identifying patients most likely to respond to immunotherapy is an important challenge for our society.

With the advent of immunotherapy, cancer treatment has changed dramatically and some previously fatal cancers can now be cured. Unfortunately, not all patients respond to immunotherapy, so biomedical research is striving to understand (1) how to predict which patients will benefit and (2) how to sensitize more patients to treatment. In our team, we have identified a type of immune cell residing within tumors (macrophages) that favors the activation of another pathogenic cell type in tumors, fibroblasts. Our results suggest that as a result of this cellular interaction, immunotherapy in a very specific group of lung cancer patients becomes ineffective.

Our initial hypothesis is that disruption of this interaction between macrophages and fibroblasts will sensitize tumors to immunotherapy. To understand this cellular dialogue, we asked 3 questions: (1) Can the origin of macrophages predict which patients are most likely to benefit from immunotherapy? (2) How do macrophages and fibroblasts regulate each other and how can we interfere with this interaction to sensitize tumors to immunotherapy? (3) Can we modify the macrophage compartment to alter fibroblast permeability within tumors and promote anti-tumor T cell immunity?

We expect that the identification of pro-fibrotic mediators in macrophages will predict response to immunotherapy. We also anticipate that targeting this program will sensitize tumors to immunotherapy, opening up hopeful new therapeutic possibilities for lung cancer patients.