Previously Funded Research

Juliana Cazarin de Menezes, PhD

University of Rochester

Research Project:

The Role of BMAL1 and Circadian Disruption in Modulating Tumor Immunity and Immunotherapy Response in Lung Adenocarcinoma

Summary:

Our bodies run on a natural 24-hour cycle known as the circadian rhythm, which regulates many important functions, such as sleep, metabolism, and the immune system. Interestingly, recent research has shown that these internal clocks, which each cell in the body has, also affect how well cancer treatments work, especially a type of immunotherapy called immune checkpoint inhibitors (ICIs), which help the immune system attack tumors. This suggests that the immune system’s ability to fight cancer changes throughout the day, likely influenced by circadian rhythms.

Our main question is why timed immunotherapy might not work in some patients, and what factors might cause it to not work. One key factor involved in circadian rhythms is a protein called BMAL1, which helps control the body’s internal clock, and rhythms in cells. In lung cancer, the circadian rhythm in the cancer cells is often disrupted (which means altered or completely absent). Our research has shown that many lung tumors, especially lung adenocarcinoma (LUAD), have lower levels of BMAL1, and patients with lower BMAL1 in their tumors do not live as long. One potential reason for this is that tumors with less BMAL1 have weaker immune responses and fewer cancer-fighting cells (called CD8+ T cells) present in the tumor environment.

In mouse models of lung cancer, we found that removing BMAL1 from lung cancer cells leads to faster tumor growth, reduced immune activity, and more immune cells that can actually help the tumor instead of attacking it. Despite these findings, we still do not fully understand how disrupted circadian rhythms in cancer cells affect the success of timed immunotherapy. Nor do we know whether BMAL1 levels in human tumors can help predict how well patients will respond to immunotherapy. The first goal of this project is to understand how loss of BMAL1 in cancer cells affects the timing of immunotherapy.

We believe that when BMAL1 is missing, tumors may stop following a normal daily rhythm in their immune responses. This could make time-based treatments less effective. To test this, we will use a mouse lung cancer model that responds well to immunotherapy. In this lung cancer model, we will delete BMAL1 in some tumors, which mimics patients who have very low BMAL1 in their tumors. We will compare tumor growth and immune activity when mice are treated with immunotherapy at two different times: morning and night. We will also look closely at the immune cells and cancer cells within the tumors using advanced techniques like single-cell RNA sequencing. This will help us understand how the timing of treatment interacts with the presence or absence of BMAL1 in cancer cells.

The second goal is this project is to determine if BMAL1 can be used as a marker of immune suppression in human lung cancer. We believe that tumors with low BMAL1 are more likely to resist immunotherapy because they suppress the immune system. To explore this, we will study a group of 60 human lung tumor samples from the Wilmot Cancer Institute biobank where BMAL1 levels have already been measured. We will analyze these samples to see if BMAL1 levels are linked to key signs of immune activity, such as the presence of PD-L1 (a common target of immunotherapy), T-cell infiltration, and signs of T-cell exhaustion.

These insights could help identify which patients are more likely to benefit from immunotherapy based on BMAL1 levels. Ultimately, this research could help improve outcomes for lung cancer patients by optimizing the timing of immunotherapy and identifying new markers to guide treatment. If successful, our findings may lead to more personalized and effective approaches to cancer care, taking into account not only the genetic makeup of the tumor but also the biological clock that governs the immune system.