[R01] Selective loss of HLA gene products in driving unique breast cancer immunobiology
Ente: National Cancer Institute
Scadenza: 2031-05-31
Importo max: 695.884 EUR
Paese: US
Descrizione
Despite the success of immune checkpoint inhibition (ICI) in cancer therapy, intrinsic and acquired resistance to
therapy are common in triple-negative breast cancer (TNBC) patients and the mechanisms are poorly
understood. CD8+ cytotoxic T cell recognition of MHC-I-peptide complexes (pMHC-I) is critical for response to
ICIs in patients. Tumor cells can evade immunosurveillance and ICI via downregulation or deletion of tumorspecific Major Histocompatibility Complex I (tsMHC-I). Published data from our laboratory (Cancer Discovery,
2024) assessing tumors from TNBC patients show diverse MHC-I phenotypes, ranging from highly positive to
negative MHC-I expression, even within the same tumor. Using mixtures of isogenic MHC-I+ and MHC-I-null
tumor cells, we found natural killer (NK) cells, an innate cytotoxic effector, were highly upregulated in MHC-I
heterogeneous tumors, but not in B2m-null or MHC-I+ tumors, which was replicated in human TNBC. The
activation of NK cells is tightly regulated by inhibitory cell surface receptors specific for MHC-I (e.g. Killer cell Iglike receptors [KIR] or NKG2A) amongst others. Tumor cells lacking MHC-I expression are susceptible to NK
cell cytotoxicity and NK cell activation by combination therapies targeting NKG2A. While these data are
published, we have now taken a deeper dive into developing techniques that allow us to measure the levels of
specific MHC-I gene products in human breast cancers and have found a striking tendency for certain types of
breast cancers to lose HLA-A and/or -B, but retain C. This has not been identified before and may offer unique
insights into breast cancer immunobiology. Moreover, the implications for these HLA-specific losses on NK cell
function, biology, and targetability are unknown, and may substantially increase the breadth of breast cancer
patients who could benefit from anti-PD-1/L1 + anti-NKG2A targeted combinations, informing clinical trials in
development. We hypothesize that heterogeneity in antigen presentation in the tumor microenvironment leads
to unique and under-appreciated changes in tumor immunity, and resistance to standard PD-1/L1-targeted
immunotherapy, which can be overcome by co-targeting NK cell function. Using human tumors and relevant preclinical models, we will determine how changes in individual MHC-I molecules, whether by allelic loss (HLA-A, B
or C) or downregulation, alters anti-tumor immunity and test strategies to overcome these adaptations.
We strive to make use of New Approach Methodologies (NAMs) such as organoids, computer modeling, and
microphysiological systems at all opportunities, including in this project. However, these methodologies
insufficiently model an intact immune system, which necessitated the limited use of animal models in this
proposal.
Istituzione: VANDERBILT UNIVERSITY MEDICAL CENTER
PI: Justin M Balko
Progetto: 1R01CA303042-01A1
Settori: National Cancer Institute
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