Tumor draining lymph node immunomodulation to decrease recurrence in NSCLC

2022

Health Equity and Inclusiveness Junior Investigator Award

Jonathan Villena-Vargas, MD

Weill Medical College of Cornell University

New York

Lymph nodes are small structures that work as filters for foreign substances, such as cancer cells and infections. These nodes contain infection-fighting immune cells that are carried in through the lymph fluid. This project will study the lymph node draining basin, which is involved in the spread of a tumor from the original location site to distant sites, and whether activating cancer-fighting T-cells can decrease recurrence in NSCLC. Dr. Villena-Vargas will use animal models to investigate whether immune checkpoint inhibitors enhance lymph node T-cells memory, which increases their ability to recognize cancer cells in the bod and can prevent metastatic recurrence.

Research Summary

Approximately 25% of the patients diagnosed with non-small cell lung cancer (NSCLC) exhibit early-stage disease. Patients with early-stage (I/II) NSCLC are routinely treated by surgery, which results in local control. However, systemic relapse (metastasis) occurs in 50% patients within 5 years of surgical intervention even with additional therapy such as chemotherapy and/or radiation. Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis have revolutionized the treatment landscape, generating therapeutic efficacy in approximately 25% of patients in early and advanced stages of lung cancer. However, there are currently inconclusive studies as to 1) timing of treatment 2) optimal combination therapy 3) prediction of patient response. In order, to recapitulate early-stage lung cancer treatment and metastatic recurrence, we have established a murine model of resection and recurrence. Our preliminary data has revealed a major immune response at the level of the tumor draining lymph node (TDLN) with PD-1 checkpoint blockade. In addition, this response is primarily responsible for T-cell memory differentiation, proliferation, and survival with subsequent decrease in metastatic recurrence in responding mice. Given these results, we hypothesize that optimal therapy against metastatic recurrence will be dependent on establishment of appropriate T-cell memory “immunosurveillance”. In addition, we have shown that the memory nodal response can be augmented by utilizing a cytokine immunomodulatory combination strategy with cure in over 70% of mice. Importantly, we have characterized that these specific T-cell memory population are uniquely found in the TDLN of early-stage patients (i.e. not in the primary tumor or peripheral blood that is commonly interrogated). In this proposal we will utilize a combination of both novel preclinical mouse models and patient-derived tumor draining lymph node T cells, to dissect molecular and cellular mechanisms of “immune-memory” response or resistance to immunotherapy, the key steps in establishing immunosurveillance for freedom from metastatic recurrence.

Technical Abstract

Anti–PD-1 therapy has transformed the management of NSCLC, but only a subset of patients respond to anti–PD-1 therapy, and responses are rarely curative. Understanding the effects of anti–PD-1 therapy on the composition and functional state of tumor-associated immune subsets can identify mechanisms of response and resistance to anti–PD-1 therapy and provide insights into rational combination strategies to improve upon response rates. Although the effects of anti–PD-1 therapy within the tumor immune microenvironment in preclinical and human subjects have been previously reported, we propose to broadly characterize the effects of anti–PD-1 therapy on the tumor draining lymph nodes (TDLN). Studying the TDLN is particularly valuable because it is the primary sites at which the tumor antigen exposure and the main site of immune T-cell differentiation. To determine the effect of ICI response in the lymph node, we have created an immunocompetent murine model that recapitulates early-stage treatment and outcomes in patients. Additionally, we have characterized TDLN T cells from early-stage cancer patients and have been able to recapitulate our preclinical findings of unique memory T-cell subsets. Our preliminary results of the immune cell type composition, checkpoint expression, and cytokine expression within TDLNs suggest that there are major remodeling events within the TDLN mediated by anti–PD-1 therapy that are critical for conferring effective antitumor long-term immune responses. We demonstrate that unique memory T cell subsets undergo significant activation, expansion, and maturation in response to anti–PD-1 therapy, to shape antitumor programming in TDLNs. Importantly, our proposed study will provide a methodological demonstration in both a murine model and human TDLN that simultaneous uses Flowcytometry, functional immune assays and single cell sequencing that will enable deep interrogation of the immune profile to PD-1 inhibition resistant and responsive patients.

Tumor draining lymph node immunomodulation to decrease recurrence in NSCLC

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