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LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses

ABSTRACT: Cancer immunotherapies boost antitumor immunity and improve the survival of cancer patients. V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an immune 20 checkpoint target but presents elusive signaling mechanisms. We report a novel VISTA binding partner, Leucine-Rich Repeats and Immunoglobulin Like Domains 1 (LRIG1), which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor T cell responses. Mechanistically, LRIG1-deficient tumor-specific CD8+ cytotoxic T cells (CTLs) exhibited longer 25 persistence due to improved expansion and survival and greater effector function. Sustained tumor control was also associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In human melanoma, an elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. Taken together, these results delineate the role of LRIG1 as an inhibitory 30 immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell

DISEASE(S): Cell Type Cancer

SUBMITTER: Belinda Willard

LAB HEAD: Li Lily Wang

PROVIDER: PXD050084 | Pride | 2024-10-17

REPOSITORIES: Pride

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			Action	DRS
	WT_IP_LilyWang.mzML	Mzml
	WT_IP_LilyWang.mzid.gz	Mzid
	WT_IP_LilyWang.raw	Raw

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LRIG1 engages ligand VISTA and impairs tumor-specific CD8<sup>+</sup> T cell responses.

Ta Hieu Minh HM Roy Dia D Zhang Keman K Alban Tyler T Juric Ivan I Dong Juan J Parthasarathy Prerana B PB Patnaik Sachin S Delaney Elizabeth E Gilmour Cassandra C Zakeri Amin A Shukla Nidhi N Rupani Amit A Phoon Yee Peng YP Liu Caini C Avril Stefanie S Gastman Brian B Chan Timothy T Wang Li Lily LL

Science immunology 20240517 95

Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways ...[more]

PMID: 38758807

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