Research

Understanding how macrophages interact with cancer cells

Macrophages are often the most common immune cell present within tumors, and a greater degree of macrophage infiltration often correlates with worse patient outcomes. Macrophages can secrete growth factors, promote angiogenesis, and remodel the extracellular matrix. They can also contribute to the general immunosuppressive state of the tumor microenvironment. These functions support the growth and dissemination of cancer. In our ongoing investigations, we are studying the molecules and signaling pathways that underlie these processes. We have focused on how macrophages impair responses to conventional chemotherapy drugs as well as targeted therapies for cancers with oncogenic driver mutations.

In parallel, we have also studied which drugs make cancer cells more vulnerable to macrophage attack. Via a series of high-throughput small molecule screens, we found that targeted therapies that inhibit signaling of the MAPK pathway can prime oncogene-driven lung cancers for macrophage-mediated destruction (Vaccaro et al. 2024 J Clin Invest). We are continuing these investigations to understand the changes that occur in cancer cells that make them more sensitive to macrophage-mediated cytotoxicity, and to understand whether combination treatment strategies that engage macrophages can result in more effective anti-tumor responses. These ongoing efforts have a primary focus on non-small cell lung cancer and gastrointestinal cancers.

Engineering novel immune-based therapies to eliminate cancer

 We are pursuing a multipronged approach to discover new targets and develop new drug treatments for cancer. Via comprehensive surfaceome profiling, we have defined a compendium of surface antigens that are amenable to targeting with antibody-based therapies. We are investigating the therapeutic potential of these targets using multiple modalities, including bispecific antibodies, antibody-drug conjugates (ADCs), and CAR T-cell therapies. These efforts have generated novel therapeutic candidates and provided us with unique insight into the biology of the tumor microenvironment.

Additionally, we are investigating how the diversity of cytokines may influence anti-tumor immunity. In preliminary studies, we have identified specific cytokines that provoke the innate and adaptive immune system to attack cancer. We have leveraged this information to engineer antibody-cytokine fusion proteins that selectively deliver cytokines as an immunotherapeutic payload into the tumor microenvironment. We continue to investigate which cytokines are most effective at engaging immune cells, and which cytokines can elicit the most durable anti-tumor responses. These efforts have revealed unappreciated cellular processes that immune cells employ to eliminate cancer.

Discovering novel immune checkpoints

Immune checkpoints are critical molecules that regulate the ability of the immune system to recognize cancer cells as foreign and to mount an anti-tumor response. The CD47/SIRPa axis is the best-characterized immune checkpoint that regulates macrophages and myeloid cells in the tumor microenvironment. Yet, despite the importance of myeloid cells in tumor immunology, there have only been limited efforts to identify other signals that regulate them in the context of cancer.

We have developed an innovative platform to define the intercellular interactions between primary human macrophages and human cancer cells. Via a series of unbiased CRISPR screens and other genome-scale screening efforts, we have identified critical genes that control the ability of macrophages to engulf and destroy cancer. We are actively investigating the functions of these genes across different cancer types. We are evaluating their contribution to anti-tumor immunity with respect to macrophages and in the larger context of the immune system as a whole. Our long-term objective is to apply this information to develop novel therapies that specifically provoke macrophages to attack and eliminate cancer cells.

Research Support

  • Valhalla Foundation

  • Torrey Coast Foundation

  • National Cancer Institute R01

  • AACR-AstraZeneca Career Development Award for Physician-Scientists, in Honor of José Baselga

  • Department of Defense

  • American Lung Association Catalyst Award

  • Research Foundation for the Treatment of Ovarian Cancer

  • A Breath of Hope Foundation

  • ASCO Conquer Cancer Foundation YIA

  • SITC Holbrook Kohrt Cancer Immunotherapy Fellowship Award

  • COVID-19 Fast Grants, Emergent Ventures

  • Dr. Richard Reisman in honor of Jane Reisman and Lillian Reisman

  • Mr. and Mrs. George Carmany

  • Anonymous

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