Abstract
Characterizing the role of PIM kinases in the prostate tumor immune microenvironment.
Author
person
Amber N Clements
The University of Arizona Cancer Center, Tucson, AZ
info_outline
Amber N Clements, Sachin Kumar Deshmukh, Sharon Wu, Joanne Xiu, Alex Patrick Farrell, Milan Radovich, Elisabeth I. Heath, Rana R. McKay, Kai Sutterby, Shailender S Chauhan, Chadi Nabhan, Alejandro Recio-Boiles, Noel A Warfel
Full text
Authors
person
Amber N Clements
The University of Arizona Cancer Center, Tucson, AZ
info_outline
Amber N Clements, Sachin Kumar Deshmukh, Sharon Wu, Joanne Xiu, Alex Patrick Farrell, Milan Radovich, Elisabeth I. Heath, Rana R. McKay, Kai Sutterby, Shailender S Chauhan, Chadi Nabhan, Alejandro Recio-Boiles, Noel A Warfel
Organizations
The University of Arizona Cancer Center, Tucson, AZ, Caris Life Sciences, Phoenix, AZ, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, University of California San Diego, La Jolla, CA
Abstract Disclosures
Research Funding
No funding received
None.
Background:
The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, a family of pro-survival kinases (
PIM1, PIM2
, and
PIM3
), are frequently overexpressed in prostate cancer (PC) and associated with PC aggressiveness and immune evasion. Preclinical data indicate that PIM1 overexpression increases macrophage infiltration and survival using
in vivo
models of PC. Here, we characterized the association of
PIM1, PIM2,
and
PIM3
with PC immune signatures.
Methods:
77 primary prostate and 11 metastatic lymph node samples from treatment-naive metastatic hormone-sensitive PC pts were analyzed by DNA next-generation sequencing (592-gene, NextSeq; WES, NovaSeq) and Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). PC with
PIM1/PIM2/PIM3-
high(H) and -low(L) expression were classified by top and bottom quartile, respectively. Androgen receptor (AR) signature and Neuroendocrine Prostate Cancer (NEPC) score were calculated based on the expression level of previously defined gene signatures (Hieronymus
et al.
2006, Beltran
et al.
2016). Pathway enrichment was determined by GSEA (Broad Inst). Immune cell fractions were calculated by deconvolution of WTS using Quantiseq. Statistical significance was determined by chi-square and Mann-Whitney U (p < 0.05) and adjusted for multiple comparisons (q < 0.05).
Results:
PIM1/PIM2/PIM3
-H PC had a higher median MAPK activation score (MPAS) compared to
PIM1/PIM2/PIM3
-L PC (0.9, 1.3, 0 vs -1.6, -1.4, -1.1 respectively, all p < 0.05). There was no difference in AR signature or NEPC score between
PIM
-H and
PIM
-L PC.
PIM3
-H PC exhibited higher PSA expression (3.15-fold, p < 0.05).
PIM1/PIM2
-H PC had higher AR expression (1.9 and 3.5-fold, respectively, all p < 0.05).
PIM2/PIM3
-H PC had enrichment of
PI3K/AKT/mTOR,
IL2/STAT5,
IL6/JAK/STAT3
,
KRAS, TGFβ,
NOTCH, hypoxia signaling, and ROS,
P53
, OXPHOS pathway and EMT (NES: 1.3-1.5, all FDR < 0.25).
PIM1/PIM2
-H PC had higher expression of immunostimulatory genes (
IL1β, TNF,
and
TNFSF13
, FC: 1.1-3.1, p < 0.05).
PIM1/PIM2/PIM3
-H PC had higher expression of MHC class I (
HLA-A, HLA-B, HLA-C, B2M
, FC: 1.3-2.5, all p < 0.05) and MHC class II (
HLA-DPA1, HLA-DRB1, HLA-DPB2
,
TAP1, TAP2,
FC: 1.1-3.2, all p < 0.05) genes.
PIM3
-H PC had increased infiltration of M2 macrophages (8% vs 5.2%) and NK cells (5.2% vs 3.3%), while
PIM2
-H PC had increased Tregs (1.7% vs 0%) (all p < 0.05). Moreover
, PIM1/PIM2/PIM3
-H PC had a high T cell inflamed score compared to
PIM1/PIM2/PIM3
-L PC (66, 80, 56 vs -143, -157, -136, respectively, all p < 0.05).
Conclusions:
Our data suggest a strong association between
PIM
expression and increased MAPK activation score, T cell inflamed score, inflammatory, MHC class I and MHC class II gene expression, and differential immune cell infiltration. A better understanding of these differences will provide a rationale for tailored therapeutic approaches for
PIM-
expressing PC.
9 organizations
3 drugs
3 targets
Organization
The University of Arizona Cancer CenterOrganization
Tucson, AZOrganization
Caris Life Sciences, Irving, TXOrganization
Phoenix, AZOrganization
Karmanos Cancer InstituteOrganization
Wayne State University School of MedicineOrganization
Detroit, MIOrganization
University of California San DiegoOrganization
La Jolla, CADrug
PIM1Drug
PIM2Drug
PIM3Target
PIM2Target
PIM3Target
PIM1