NIH grant: Deciphering tumor-immune coevolution during metastatic progression (1U01CA313445-01)

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NIH grant 1U01CA313445-01: Deciphering tumor-immune coevolution during metastatic progression
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Nathan Edward Reticker-Flynn. Award: $605108.
Start: 2026-08-07T00:00:00.
Metastasis is responsible for most deaths related to solid organ malignancies. Throughout every step of metastasis, tumors encounter immune cells, including lymphocytes. These lymphocytes are capable of recognizing tumor-specific antigens and eliminating the tumors. Thus, the balance between the continuous evolution of tumors and the ability of lymphocytes to recognize and eliminate them represents an essential determinant of survival. This balance is especially important during metastasis. While low mutational burden tumors may evade immune surveillance through the loss of neoantigens, tumors such as melanoma and head and neck cancers must evolve additional mechanisms to avoid elimination during metastasis. In
evolutionary biology, the reciprocal adaptations of species is a defining hallmark of coevolution. While there is a growing appreciation that microenvironmental factors affect tumor progression, applications of coevolution principles have been limited to pruning of neoantigens. We hypothesize that tumor-immune interactions during metastasis lead to coevolution of the tumors and lymphocytes in concordance with models of antagonistic coevolution. We have previously discovered that early-stage metastatic tumors can exploit immune education within lymph nodes (LNs) to alter adaptive immune responses, thus facilitating further tumor dissemination. Here, we leverage our mouse models of metastasis and head and neck cancer
patient samples to uncover the mechanisms of tumor-immune coevolution from the earliest stages of metastasis to widespread distant disease. A hallmark of coevolution is the resultant increase in heterogeneity of both species. Here, we nterrogate the evolutionary dynamics of clonotypic and phenotypic heterogeneity of tumors and lymphocytes. We investigate how tumors adapt during dissemination to LNs and distant tissues and the roles of the adaptive immune response in shaping heterogeneity. Using genomic barcoding, transcriptional and epigenetic profiling, and spatial transcriptomics, we explore how the adaptive immune microenvironment of distinct tissues alters the evolutionary states of the tumors. We explore how tumors promote counteradaptations in lymphocytes using antigen receptor repertoire profiling. Finally, we interrogate whether the adaptations that confer metastatic potential can be therapeutically targeted to treat metastatic disease in mice and humans. This project makes use of vertebrate animals, specifically mouse models, which enable us to evaluate how tumors spread throughout different tissues in the body, how immune responses are altered in these different tissue environments over time, and how immunotherapy can affect these immune responses across different tissues. These analyses cannot be performed using in vitro co-culture systems or correlative patient analyses alone as they involve crosstalk between organs. At the conclusion of this project, we will uncover how tumor-immune coevolution alters metastatic fate and the features that could be targeted to shift the balance in favor of anti-tumor immunity.

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