Differential regulation of TNFα and IL-6 expression contributes to immune evasion in prostate cancer

• DOI: 10.1186/s12967-022-03731-x
• Publication Date: 2022-11-12T09:03:04Z
• Authors: Ida Deichaite; Timothy J. Sears; Leisa Sutton; Daniel Rebibo; Kylie Morgan; Tyler Nelson; Brent Rose; Pablo Tamayo; Napoleone Ferrara; Fotis Asimakopoulos; Hannah Carter
• Keywords: Urologic Diseases; Male; 0301 basic medicine; Aging; Biomedical and clinical sciences; macrophage polarization; Clinical Sciences; Oncology and Carcinogenesis; Immunology; TNF; 610; bevacizumab; Immune remodeling; Medical and Health Sciences; 03 medical and health sciences; FOSB; 616; Tumor Microenvironment; 2.1 Biological and endogenous factors; Humans; Cancer; Immune Evasion; Inflammation; IL-6; Prostate cancer; Biomedical and Clinical Sciences; Interleukin-6; Tumor Necrosis Factor-alpha; Prostate Cancer; Inflammatory and immune system; Research; R; immune remodeling; Health sciences; Prostatic Neoplasms; ADAMTS-4; SELE; prostate cancer; AP-1; 3. Good health; Bevacizumab; Macrophage polarization; Medicine; Tumor Necrosis Factor Inhibitors

Abstract Background The role of the inflammatory milieu in prostate cancer progression is not well understood. Differences in inflammatory signaling between localized and metastatic disease may point to opportunities for early intervention.

Methods We modeled PCa disease progression by analyzing RNA-seq of localized vs. metastatic patient samples, followed by CIBERSORTx to assess their immune cell populations. The VHA CDW registry of PCa patients was analyzed for anti-TNF clinical outcomes.

Results We observed statistically significant opposing patterns of IL-6 and TNFα expression between localized and metastatic disease. IL-6 was robustly expressed in localized disease and downregulated in metastatic disease. The reverse was observed with TNFα expression. Metastatic disease was also characterized by downregulation of adhesion molecule E-selectin, matrix metalloproteinase ADAMTS-4 and a shift to M2 macrophages whereas localized disease demonstrated a preponderance of M1 macrophages. Treatment with anti-TNF agents was associated with earlier stage disease at diagnosis.

Conclusions Our data points to clearly different inflammatory contexts between localized and metastatic prostate cancer. Primary localized disease demonstrates local inflammation and adaptive immunity, whereas metastases are characterized by immune cold microenvironments and a shift towards resolution of inflammation and tissue repair. Therapies that interfere with these inflammatory networks may offer opportunities for early intervention in monotherapy or in combination with immunotherapies and anti-angiogenic approaches.