Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline.
DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests, with corrections for multiple comparisons where appropriate.
In both a pan-tumor and prostate cancer (PCa) -specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2-9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response.
Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.
Prostate cancer and prostatic diseases. 2024 Feb 28 [Epub ahead of print]
Nicholas A Zorko, Allison Makovec, Andrew Elliott, Samuel Kellen, John R Lozada, Ali T Arafa, Martin Felices, Madison Shackelford, Pedro Barata, Yousef Zakharia, Vivek Narayan, Mark N Stein, Kevin K Zarrabi, Akash Patniak, Mehmet A Bilen, Milan Radovich, George Sledge, Wafik S El-Deiry, Elisabeth I Heath, Dave S B Hoon, Chadi Nabhan, Jeffrey S Miller, Justin H Hwang, Emmanuel S Antonarakis
Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, MN, USA. ., Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, MN, USA., Caris Life Sciences, Phoenix, AZ, USA., University Hospital Seidman Cancer Center, Cleveland, OH, USA., Holden Comprehensive Cancer Center, Iowa City, IA, USA., Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., Herbert Irving Comprehensive Cancer Center, Columbia University New York, New York, NY, USA., Sidney Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA, USA., University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA., Winship Cancer Institute of Emory University, Atlanta, GA, USA., Legorreta Cancer Center, Brown University, Providence, RI, USA., Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA., Saint John's Cancer Institute, Saint John's Health Center PHS, Santa Monica, CA, USA.