Immunotherapies today primarily rely on T cells to achieve results in patient treatment. Understanding how T cells become exhausted and developing ways to reinvigorate them or prevent them from becoming exhausted in the first place is a central question that CRI scientists are determined to answer. Their hope is that these answers will lead to new therapeutic strategies that improve overall patient responses to immune checkpoint blockade and other T cell-based immunotherapy approaches.

An effective T cell-mediated immune response requires T cells to locate cells that carry specific targets, or antigens, that activate the T cell’s cancer-killing power. Other molecular signals that act as fail safes must also be engaged to initiate cell killing. If a cancer cell does not express the target, T cells will not recognize it as a threat and will move on. Cancer cells that escape the immune system in this way often can do so by losing these markers as tumors evolve. By masking their identities, these cancer cells go on to develop into tumors and can progress to disease.

CRI Clinic and Laboratory Integration Program Investigator Toni Celià-Terrassa, Ph.D., at the Hospital del Mar Medical Research Institute in Spain discovered a way to enhance the responses to treatment with checkpoint blockade among women with triple-negative breast cancer (TNBC). TNBC lacks three specific characteristics required for treatment with most available breast cancer therapies and is therefore considered especially hard to treat. When TNBC also lacks targets that the immune system “sees,” patients typically respond poorly to checkpoint blockade treatment. Dr. Celià-Terrassa, however, identified a specific transcription factor called ligand-dependent corepressor, or LCOR, that forces TNBC cells to express their abnormal antigens, making them visible to the immune system. His promising approach has the potential to benefit patients with TNBC and other hard-to-treat cancers that escape the immune system.

Myeloid cells are a group of immune cells that originate and mature in the bone marrow. These cells are major actors in mediating patient immune responses and cancer immunotherapy treatment outcomes. This stems from their ability to either promote or inhibit T cells responses. This family of cells includes macrophages, dendritic cells, granulocytes, and monocytes, among others, and they can contribute to the aggressiveness of cancer growth and spread throughout the body.

Macrophages are particularly important to the process of immune response mediation. Like generals, they dictate the course of the engagement and often determine whether the immune system and cancer-killing T cells will be suppressed or emerge victorious. Tumors, however, have an unsettling ability to convert a patient’s macrophages from defenders to turncoats, recruiting them in aiding cancer instead of fighting it.

How tumors do this is a key question in cancer immunology. Discovering the molecular mechanisms that give tumors the power to “turn” macrophages may provide valuable targets for new immunotherapies, unlocking new treatment strategies.

Ping-Chih Ho, Ph.D., a CRI Lloyd J. Old STAR at Ludwig Cancer Research and the University of Lausanne in Switzerland, recently revealed one way that tumors manipulate these macrophages. By producing molecules called glucosylceramides, tumors can disrupt the composition of macrophage membranes and induce internal cellular stress that results in immune suppression. This behavior, Dr. Ho discovered, depended on the presence of a transcription factor involved in inflammation, XBP1, which activates genes within the macrophage that transform them into immuno-suppressive, pro-tumor agents. Targeting this factor therapeutically is one potential approach to preventing this kind of cellular betrayal.

Myeloid cells also play a prominent role in immunotherapy-resistant pancreatic cancers. Here, the build-up of damaging reactive nitrogen species (RNS) acts as a barrier that keeps T cells at bay. Vincenzo Bronte, M.D., a CRI CLIP Investigator at the University of Verona in Italy, explored how we might reprogram myeloid cells and reverse the situation. In mice, Dr. Bronte demonstrated that an FDA-approved antiviral, remdesivir, blocks enzymes that produce the nitrogen compounds, making a type of immunotherapy called adoptive T cell transfer more successful. This work will be advanced through preclinical and potentially clinical studies to test whether this approach may be an effective way to improve the responses of patients receiving adoptive T cell therapy.