Antigen Presentation Inhibitors for Cancer Immunotherapy

ASPIRE Award (2021-Present)

Jun Wang, PhD (Principal) and Iannis Aifantis, PhD, New York University

Jun Wang, PhD

Iannis Aifantis, PhD

Antigen presentation is a key process that occurs in all nucleated cells in the body. During antigen presentation, fragments from intracellular proteins are exposed to the extracellular environment by a class of molecules known as the major histocompatibility complex class (MHC). Antigen presentation serves as a surveillance mechanism for the immune system and underlies T cell-based immunity to both intracellular pathogens and highly mutated tissues like cancer. Under healthy conditions, cells present peptides derived from the host proteome, which are recognized as “self” and are not targeted for destruction by T cells. However, tumor cells with high levels of DNA damage present peptides from mutated proteins, which the immune system treats as “foreign”; these peptides signal to T cells to destroy the cancerous cells. Indeed, the enhancement of this system is the basis for immune checkpoint blockade therapy that has revolutionized cancer treatment. However, cancer cells often evolve mechanisms to suppress MHC expression in order to evade the immune system, leading to eventual resistance. Therefore, new ways to understand and counter this downregulation of MHC are necessary.

Previously, Jun Wang and Iannis Aifantis developed a CRISPR screen to identify new cellular activators and inhibitors of antigen presentation, and have identified two proteins that suppress MHC class 1 expression. Here, they will explore the molecular mechanism of action behind this suppression, test the expression level of these proteins in different cancer tissues, and explore whether they represent therapeutic opportunities to improve immunotherapy. These studies will facilitate our understanding of tumor-associated immune evasion mechanisms and deliver antigen presentation-targeted cancer immunotherapies.

published research

Chen X, Lu Q, Zhou H, Liu J, Nadorp B, Lasry A, Sun Z, Lai B, Rona G, Zhang J, Cammer M, Wang K, Al-Santli W, Ciantra Z, Guo Q, You J, Sengupta D, Boukhris A, Zhang H, Liu C, Cresswell P, Dahia PLM, Pagano M, Aifantis I, Wang J. A membrane-associated MHC-I inhibitory axis for cancer immune evasion. Cell. 2023.

Wang J, Lu Q, Chen X, Aifantis I. Targeting MHC-I inhibitory pathways for cancer immunotherapy. Trends Immunol. 2024.

Philips EA, Liu J, Kvalvaag A, Mørch AM, Tocheva AS, Ng C, Liang H, Ahearn IM, Pan R, Luo CC, Leithner A, Qin Z, Zhou Y, Garcia-España A, Mor A, Littman DR, Dustin ML, Wang J, Kong XP. Transmembrane domain-driven PD-1 dimers mediate T cell inhibition. Sci Immunol. 2024.

Silberstein JL, Du J, Chan KW, Frank JA, Mathews II, Kim YB, You J, Lu Q, Liu J, Philips EA, Liu P, Rao E, Fernandez D, Rodriguez GE, Kong XP, Wang J, Cochran JR. Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function. Proc Natl Acad Sci U S A. 2024.