Correlation of PIM kinases with tumor immune microenvironment and clinical presentation of metastatic hormone-sensitive prostate cancer

Authors:

Alejandro Recio-Boiles, Amber N Clements, Sachin Kumar Deshmukh, Aaron Bertolo, Ricardo J. Estrada-Mendizabal, Kathylynn Saboda, Sharon Wu, Joanne Xiu, Milan Radovich, Kai Sutterby, Shailender S Chauhan, Rana R. McKay, Chadi Nabhan, Noel A Warfel

Background: The Proviral Integration site for Moloney murine leukemia virus (PIM1, 2, and 3) kinases are frequently overexpressed in prostate cancer (PC) and associated with aggressiveness and immune evasion. PIM overexpression increases macrophage infiltration and survival in in vivo models of PC. Here, we characterized the association of PIM1/2/3 triplet-combined High versus Low with PC immune signatures on real-world patients’ clinical presentation.

Methods: 44 patients of treatment-naive metastatic hormone-sensitive PC (mHSPC) patients (pts) samples were analyzed by next-generation sequencing (592, NextSeq; WES, NovaSeq), (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). PC with PIM1/2/3-high(H) (N=28) and -low(L) (N=16) expressions were classified by top and bottom quartile, respectively. Pathway enrichment was determined by GSEA (Broad Inst). Immune cell fractions were calculated by deconvolution of WTS using Quantiseq. Statistical significance was determined by MannWhitney U and adjusted for multiple comparisons (p,0.05). Continuous and categorical variables were evaluated using t-tests or Kruskal-Wallis Rank sum tests and Chi-square or Fisher’s exact tests, respectively.

Results: mHSPC pts median ages were 67.28 (SD 10.65), 88% White, 44% non-Hispanic, ECOG ,2 95% and other demographics showed no differences between PIM-H and L. PIM-H vs L tumors presentation was 48 vs 35% Gleason .9, 82 vs 57% T.3, 76 vs 69% N1, and 92 vs 81% M1, all p.0.05. Median PSA levels at diagnosis were 66.0 [14.0-450.7] vs 24.0 [6.6-95.0] by PIM-H and L, p=0.14. PIM-H had a higher median MAPK activation score compared to PIM-L PC (0.85 vs -1.38, q,0.05). PIM-H PC exhibited higher PSA (548.2 vs 213.2) and AR (118.6 vs 50.8) expression, all q,0.05. PIM-H had enrichment of protein secretion signaling pathway (NES: 1.2; FDR ,0.25). PIM-H had higher expression of immunostimulatory (IL1b, TNF, IL-2, and TNFSF13, FC: 1.9-3.1, p,0.05) and hypoxia-related genes (HIF1⍺, ARNT, VEGFA, PDGFB, LDHA, NDRG1, SLC2A, PGK1, and DDIT4, FC: 1.3-2.4, p,0.05). PIM-H had higher expression of MHC class I (HLA-A, -B, -C, TAP1, TAP2, B2M, FC: 1.9-2.2, all p,0.05) and MHC class II (HLA-DPA1, -DRB1, -DPB2, -DQB2, -DBP1, -DQB1 FC: 1.8-3.2, all p,0.05) genes. PIM-H had increased infiltration of B cells, M2 MØ and NK cells (all p ,=0.05). PIM-H PC had a higher T cell inflamed score (70 vs -138, p,0.05).

Conclusions: These data indicate a strong association of PIM expression with increased MAPK activation score, T cell inflamed score, inflammatory, PSA, AR, MHC class I and MHC class II gene expression, and differential immune cell infiltration. However, this did not significantly translate to a worse clinical presentation of mHSPC. A better understanding of these differences with additional research may provide a rationale for tailored therapeutic approaches for PIM-expressing mHSPC.