Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma.

BACKGROUND

Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets.

METHODS

We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort.

RESULTS

Unsupervised clustering identified two "TME subtypes", in each of the cohorts: the "immune-enriched" and the "immune-low". Within AXIPAP trial cohort, the "immune-enriched" cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the "immune-enriched" group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations.

CONCLUSION

For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This "immune-enriched" group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies.

TRIAL REGISTRATION NUMBER

NCT02489695.

Informations de copyright

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: MdV-B: Research Grant: Ipsen. Board: AstraZeneca, AAA, BMS, Astellas. Travel expense: Pfizer. NR-L: Board: Ipsen, BMS, AstraZeneca. RF: Honoraria: Merck, Pfizer, Ipsen, MSD, Bayer. Board: Janssen, Merck, Pfizer. Expert: Ipsen, Janssen, Astellas. GG: Speaker bureau: Janssen, Amgen, BMS, Ipsen, AAA, AstraZeneca, Bayer, Pfizer, Merck, Astellas. Recipient my institution. Board: Janssen, Amgen, BMS, Curium, Bayer, Pfizer, Merck. Recipient my institution. Expert: BMS, Bayer, Pfizer, Merck. Recipient my institution. Travel expense: Janssen, BMS, AstraZeneca, Bayer, Pfizer Merck. Recipient: me. LG: Consulting or advisory role: BMS, MSD, Novartis, Ipsen, Janssen. CC: Consulting or advisory role: Pfizer, Novartis, BMS. FR: Consulting: Pfizer, Ipsen, BMS, MSD. AR: Consulting or advisory role: Pfizer, BMS, AstraZeneca, Roche, MSD, Ipsen. Travel expenses: Pfizer, BMS, AstraZeneca, Roche, MSD, Ipsen ; Institutional Grant: Pfizer. MG-G: Honoraria and travel expenses: Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Roche and Sanofi. BE: Advisory role: BMS, Pfizer, Novartis, Oncorena, Immunicum. Research grants: BMS, Novartis, Aveo. SN: Honoraria: Pfizer, Ipsen, MSD, BMS, Eisaï. Travel expenses: Pfizer, Ipsen, MSD. Research grant (institution): Pfizer, Ipsen. LA: Advisory role (Institution): BMS, MSD, Pfizer, Novartis, Amgen, Astellas, Ipsen, Roche, Merck, AstraZeneca, Exelixis, Peloton therapeutics, Corvus pharmaceuticals, Janssen, Eisai, 4D Pharma. Travel expenses: Merck/Pfizer. MM, JD, CP, ES-M, GF, EB, FL: no conflict.