(P 244) INTRATUMORAL TIGIT BLOCKADE AUGMENTS ANTI-TUMOR RESPONSES AND BYPASSES HYPERFUNCTIONALITY OF PERIPHERAL TIGIT+ NK CELLS IN MOUSE AND HUMAN MODELS OF BONE AND SOFT TISSUE SARCOMA

Co-Author(s)

Sylvia M. Cruz, MD (she/her/hers)

Resident Physician
Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
ML

Marshall Lammers, BS

Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
Cyrus J. Sholevar, MD

Resident Physician
Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
AR

Aryana M. Razmara, BS

Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
MP

Megan Purl, BS

Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
NL

Natalie Liu, MD

Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
DB

Danika Bakke, PhD

Caris Life Sciences
Phoenix, Arizona, United States
MS

Michael Sheng, BS

Department of Dermatology, University of California, Davis
Sacramento, California, United States
RN

Ryan Nielsen, BS

Department of Dermatology, University of California, Davis
Sacramento, California, United States
TK

Tushar Kotamraju, N/A

Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
LF

Lauren E. Farley, BS

Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
KI

Khurshid R. Iranpur, BS

Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States
TM

Trasneem Mukarrama, BS

Biomedical Engineering, University of California, Davis
Sacramento, California, United States
AM

Arta M. Monjazeb, MD, PhD

Radiation Oncology, University of California, Davis
Sacramento, California, United States
Steven W. Thorpe, MD (he/him/his)

Associate Professor
Orthopedic Surgery, University of California, Davis
Sacramento, California, United States
MD

Morgan A. Darrow, MD

Associate Clinical Professor
Pathology and Laboratory Medicine, University of California, Davis
Sacramento, California, United States
JK

Jinhwan Kim, PhD

Biomedical Engineering, University of California, Davis
Sacramento, California, United States
WM

William J. Murphy, PhD

Department of Dermatology, University of California, Davis
Sacramento, California, United States
Sean J. Judge, MD, MS

Resident in Surgery
Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States

Author(s)

Robert J. Canter, MD

Professor Surgery and Division Chief
Surgical Oncology, Department of Surgery, University of California, Davis
Sacramento, California, United States

Objective: Although TIGIT has been shown to be a key exhaustion marker in NK cells, recent data have suggested that a subset of TIGIT expressing NK cells can be hyperfunctional. We hypothesized that TIGIT+ peripheral blood NK cells are hyperfunctional, limiting efficacy of systemic TIGIT blockade. We further hypothesized that intra-tumoral administration of TIGIT blockade would overcome limitations of systemic administration.

Methods: Human and murine NK cells were analyzed from human patients and mice with osteosarcoma (OSA) and soft tissue sarcoma (STS) using flow cytometry, immunohistochemistry, live cell imaging, and RNA sequencing. TIGIT blockade was delivered systemically and intratumorally in both orthotopic and flank models of OSA (K7M2) and STS (MCA-205). Clinical and genomic data were evaluated using CARIS codeAI™. CD155 expression on myeloid cells and tumor targets was evaluated as a rheostat of TIGIT hyperfunction/dysfunction, and recombinant CD155 was used to induce dysfunction on TIGIT expressing hyperfunctional NK cells.

Results: TIGIT+ NK cells from the periphery of tumor-bearing mice, STS, and OSA patients were hyperfunctional using degranulation and Incucyte killing assays. In contrast, TIGIT+ NK cells from the sarcoma TME were more dysfunctional than TIGIT- NK cells with upregulation of senescence and chemotaxis gene expression pathways. Intratumoral administration of TIGIT blockade significantly delayed tumor growth and prolonged survival in murine OSA with partial reversal of NK dysfunction in the TME. Clinical and genomic data demonstrated that NK cell infiltration in human STS was significantly more predictive of survival when CD155 expression was low, and exposure to CD155 induced dysfunction in human peripheral TIGIT+ NK cells.

Conclusion: We identified context dependent effects of TIGIT expression on NK cell phenotype and function with peripheral TIGIT+ NK cells showing hyperfunction and intra-tumoral TIGIT+ NK cells showing dysfunction. Intratuomoral delivery of TIGIT blockade prolonged mouse survival, suggesting that this strategy may have impact for bone and soft tissue sarcomas.