Dependence of radiosensitivity of lymphocyte subtypes on proton dose and LET and its impact on immune suppression

Radiation-induced lymphopenia (RIL) is a common adverse effect of radiation therapy. Recent studies have shown that the development of severe (grades 3 or 4) RIL has a significant detrimental association with overall survival. RIL is also associated with reduced efficacy of anti-PD1 immunotherapy, which is concerning because of the considerable potential of combining radiation therapy with immunotherapy in order to take advantage of the immunostimulatory effects of radiation. Therefore, it is important to better understand the mechanisms of RIL in order to reduce patient risk. Clinical studies by our team have demonstrated that proton therapy, because of its compact dose distributions, leads to significant reduction in severe RIL and to improved outcomes. The long- term goal of this research is to be able to predict which patients are more likely to develop severe RIL and produce optimized proton treatment plans that will reduce this risk. The objective of this study is to understand how proton linear energy transfer (LET), in addition to dose, contributes to the death of lymphocytes and their subtypes. The compact dose distribution from proton therapy should theoretically reduce the incidence of RIL, but higher LET outside of the treatment site may diminish this advantage. This may explain why some studies have shown reduced incidence of RIL when the patient is treated with protons while other studies have not shown this association. The role of LET in lymphocyte death and RIL has been largely ignored. Currently, there are no data, to our knowledge, on the sensitivity of lymphocytes to LET. Further, none of the current lymphopenia risk models incorporate LET and it is not used as a parameter for plan evaluation at most proton centers. In Aim 1, I will characterize the sensitivity of lymphocytes and their subtypes to radiation dose and LET using a specialized irradiation device to expose lymphocytes simultaneously to a range of doses and LETs. In Aim 2, I will incorporate LET into the RIL risk prediction model that has been developed by our lab and test if this improves the model’s predictive power. In Aim 3, I will develop the methodology to utilize LET-guided treatment optimization, considering differential radiosensitivity of lymphocyte subtypes on LET, and assess the effectiveness of this approach for RIL risk reduction. With well regarded expertise in proton therapy and a strong medical physicist training record, the Mohan lab is an ideal environment for me to complete the proposed research. Throughout my graduate training, I will work collaboratively with several renowned scientists in multiple fields including medical physics, immunology, radiobiology, and bioinformatics from MD Anderson and our collaborating institutions. I will have access to world-class facilities including a proton center to conduct my research. Additionally, I will submit four first-authored publications, present my work regularly, and attend national and international conferences. I will also take additional coursework on immunology and bioinformatics and learn about the clinical roles of medical physicists through specialized clinical training and shadowing. Project Number: 1F31HL176043-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Madison Grayson | Institution: UNIVERSITY OF TX MD ANDERSON CAN CTR, HOUSTON, TX | Award Amount: $37,598 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F09B-Z (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17604301A1