Geospatial characterization of immune cell distributions and dynamics across the microenvironment in clear cell renal cell carcinoma

Nicholas H Chakiryan; Youngchul Kim; Anders Berglund; Andrew Chang; Gregory J Kimmel; Ali Hajiran; Jonathan Nguyen; Carlos Moran-Segura; Daryoush Saeed-Vafa; Esther N Katende; Neale Lopez-Blanco; Jad Chahoud; Phillip Rappold; Philippe E Spiess; Michelle Fournier; Daniel Jeong; Liang Wang; Jamie K Teer; Jasreman Dhillon; Fengshen Kuo; Abraham Ari Hakimi; Philipp M Altrock; James J Mulé; Brandon J Manley

doi:10.1136/jitc-2022-006195

Geospatial characterization of immune cell distributions and dynamics across the microenvironment in clear cell renal cell carcinoma

J Immunother Cancer. 2023 Apr;11(4):e006195. doi: 10.1136/jitc-2022-006195.

Authors

Nicholas H Chakiryan^{1

2}, Youngchul Kim³, Anders Berglund³, Andrew Chang¹, Gregory J Kimmel⁴, Ali Hajiran¹, Jonathan Nguyen⁵, Carlos Moran-Segura⁵, Daryoush Saeed-Vafa⁵, Esther N Katende¹, Neale Lopez-Blanco⁵, Jad Chahoud¹, Phillip Rappold⁶, Philippe E Spiess¹, Michelle Fournier⁷, Daniel Jeong⁸, Liang Wang⁹, Jamie K Teer³, Jasreman Dhillon⁵, Fengshen Kuo⁶, Abraham Ari Hakimi⁶, Philipp M Altrock¹⁰, James J Mulé^{11

12

13}, Brandon J Manley^{14

4}

Affiliations

¹ Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
² Translational Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA.
³ Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
⁴ Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
⁵ Department of Pathology, H Lee Moffitt Cancer Center, Tampa, Florida, USA.
⁶ Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁷ Tissue Core, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
⁸ Department of Radiology, H Lee Moffitt Cancer Center, Tampa, Florida, USA.
⁹ Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
¹⁰ Department of Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Ploen, Germany.
¹¹ Department of Immunology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
¹² Radiation Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
¹³ Cutaneous Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
¹⁴ Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA Brandon.Manley@moffitt.org.

Abstract

Introduction: In clear cell renal cell carcinoma (ccRCC), tumor-associated macrophage (TAM) induction of CD8+T cells into a terminally exhausted state has been implicated as a major mechanism of immunotherapy resistance, but a deeper biological understanding is necessary.

Methods: Primary ccRCC tumor samples were obtained from 97 patients between 2004 and 2018. Multiplex immunofluorescence using lymphoid and myeloid markers was performed in seven regions of interest per patient across three predefined zones, and geospatial analysis was performed using Ripley's K analysis, a methodology adapted from ecology.

Results: Clustering of CD163+M2 like TAMs into the stromal compartment at the tumor-stroma interface was associated with worse clinical stage (tumor/CD163+nK(75): stage I/II: 4.4 (IQR -0.5 to 5.1); stage III: 1.4 (IQR -0.3 to 3.5); stage IV: 0.6 (IQR -2.1 to 2.1); p=0.04 between stage I/II and stage IV), and worse overall survival (OS) and cancer-specific survival (CSS) (tumor/CD163+nK(75): median OS-hi=149 months, lo=86 months, false-discovery rate (FDR)-adj. Cox p<0.001; median CSS-hi=174 months, lo=85 months; FDR-adj. Cox p<0.001). An RNA-seq differential gene expression score was developed using this geospatial metric, and was externally validated in multiple independent cohorts of patients with ccRCC including: TCGA KIRC, and the IMmotion151, IMmotion150, and JAVELIN Renal 101 clinical trials. In addition, this CD163+ geospatial pattern was found to be associated with a higher TIM-3+ proportion of CD8+T cells, indicative of terminal exhaustion (tumor-core: 0.07 (IQR 0.04-0.14) vs 0.40 (IQR 0.15-0.66), p=0.05).

Conclusions: Geospatial clustering of CD163+M2 like TAMs into the stromal compartment at the tumor-stromal interface was associated with poor clinical outcomes and CD8+T cell terminal exhaustion.

Keywords: CD8-Positive T-Lymphocytes; Kidney Neoplasms; Macrophages; Tumor Microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

CD8-Positive T-Lymphocytes
Carcinoma, Renal Cell*
Humans
Kidney Neoplasms*
Prognosis
Tumor Microenvironment

Abstract

Publication types

MeSH terms

Grants and funding