Understanding B cell dynamics in Tertiary Lymphoid Structures and their therapeutic implications in lung cancer
Lead Research Organisation:
The Francis Crick Institute
Department Name: Research
Abstract
Targeted therapies for combating KRAS-driven lung adenocarcinoma (LUAD), a leading cause of cancer-related mortality, have been developed during the last few years. Although there have been promising results in the use of KRASG12C inhibitors (G12Ci), drug resistance remains a limitation. In contrast, immunotherapy, particularly PD-1 checkpoint inhibition, has shown durable responses in some lung cancer patients. However, not all patients respond to immune checkpoint blockade (ICB), underscoring the need to find predictive markers. Tertiary lymphoid structures (TLS) within tumors have emerged as potential indicators of favorable clinical outcomes. TLS are ectopic aggregates of lymphocytes and antigen-presenting cells that develop at sites of chronic inflammation. Notably, TLS orchestrate robust B cell responses against tumor antigens within the tumor microenvironment, fostering clonal expansion, somatic hypermutation, and antibody production. However, investigating the mechanisms by which TLS and B cells contribute to anti-tumor immune responses and immunotherapy remains challenging due to the absence of pre-clinical mouse models that induce B cell responses and respond to ICB. In addition, it has been shown that KRAS inhibitors synergize with ICB when treating immunogenic tumors to enhance T cell responses. Conversely, the role of B cells in response to KRAS targeted therapies is currently unclear.
Recent work from our laboratory has described a novel immunogenic mouse model for KRAS-driven lung adenocarcinoma that expresses antigens derived from endogenous retroviruses (ERV) and stimulates TLS formation in vivo. I hypothesize that ERV proteins can act as potent tumor antigens enhancing the formation of TLS, which modulate the function of B cells to boost strong anti-tumor immune responses. These adaptive immune responses can be further enhanced by the inhibition of KRAS, which, in combination with immunotherapies, could potentially result in durable responses in patients. Hence, my Aims are (1) to dissect the immunogenic potential of the ERV proteins in KRAS lung cancer, (2) to track and characterize the in vivo spatial and temporal dynamics of B cells in TLS, and (3) to investigate the impact of KRAS inhibition on TLS formation and B cell responses and to identify specific vulnerabilities to predict and improve LUAD outcome.
By combining immunogenic and non-immunogenic preclinical lung cancer models generated in our lab with state-of-the-art techniques, I will provide a deeper understanding of TLS-associated B cell responses against tumor antigens in KRAS-driven lung cancer. First, different in vivo models in which ERV expression is temporally controlled will be used to gain insights into the immunogenic potential of ERV antigens to boost TLS formation and anti-tumor B cell responses. Next, I will perform a time-course study of TLS formation using whole tissue spatial transcriptomics and imaging mass cytometry (IMC) by comparing TLS-containing tumors and TLS-negative tumors. These data will uncover the intrinsic cues that drive TLS formation, B cell recruitment, and the signaling pathways involved. Next, I will use multi-omic technologies to assess the impact of KRAS inhibition on B cells. Finally, I will analyze resistant tumors and serum samples from an ongoing clinical trial with LUAD patients treated with G12Ci, to understand how KRAS inhibitors shape B cell immune responses, aiming to find predictive biomarkers and improve disease outcome.
Altogether, this project will offer a unique and comprehensive approach to studying previously unknown interactions and uncovering how B cells within TLS may influence therapeutic response, aiming to find strategies to boost B cell activity in non-responsive patients. By characterizing B cell anti-tumor immune potential and cues for TLS induction, this study will shed light on improving therapy options for KRAS-driven LUAD patients.
Recent work from our laboratory has described a novel immunogenic mouse model for KRAS-driven lung adenocarcinoma that expresses antigens derived from endogenous retroviruses (ERV) and stimulates TLS formation in vivo. I hypothesize that ERV proteins can act as potent tumor antigens enhancing the formation of TLS, which modulate the function of B cells to boost strong anti-tumor immune responses. These adaptive immune responses can be further enhanced by the inhibition of KRAS, which, in combination with immunotherapies, could potentially result in durable responses in patients. Hence, my Aims are (1) to dissect the immunogenic potential of the ERV proteins in KRAS lung cancer, (2) to track and characterize the in vivo spatial and temporal dynamics of B cells in TLS, and (3) to investigate the impact of KRAS inhibition on TLS formation and B cell responses and to identify specific vulnerabilities to predict and improve LUAD outcome.
By combining immunogenic and non-immunogenic preclinical lung cancer models generated in our lab with state-of-the-art techniques, I will provide a deeper understanding of TLS-associated B cell responses against tumor antigens in KRAS-driven lung cancer. First, different in vivo models in which ERV expression is temporally controlled will be used to gain insights into the immunogenic potential of ERV antigens to boost TLS formation and anti-tumor B cell responses. Next, I will perform a time-course study of TLS formation using whole tissue spatial transcriptomics and imaging mass cytometry (IMC) by comparing TLS-containing tumors and TLS-negative tumors. These data will uncover the intrinsic cues that drive TLS formation, B cell recruitment, and the signaling pathways involved. Next, I will use multi-omic technologies to assess the impact of KRAS inhibition on B cells. Finally, I will analyze resistant tumors and serum samples from an ongoing clinical trial with LUAD patients treated with G12Ci, to understand how KRAS inhibitors shape B cell immune responses, aiming to find predictive biomarkers and improve disease outcome.
Altogether, this project will offer a unique and comprehensive approach to studying previously unknown interactions and uncovering how B cells within TLS may influence therapeutic response, aiming to find strategies to boost B cell activity in non-responsive patients. By characterizing B cell anti-tumor immune potential and cues for TLS induction, this study will shed light on improving therapy options for KRAS-driven LUAD patients.
