Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma

Manon de Vries-Brilland (1) , Nathalie Rioux-Leclercq (2, 3) , Maxime Meylan (4, 5) , Jonathan Dauvé (1) , Christophe Passot (1) , Elena Spirina Menand (1) , Ronan Flippot (6) , Gaëlle Fromont-Hankard (7) , Gwenaelle Gravis (8) , Lionnel Geoffrois (9) , Christine Chevreau (10) , Frédéric Rolland (11) , Ellen Blanc (12) , Félix Lefort , Alain Ravaud , Marine Gross‐goupil , Bernard Escudier (13) , Sylvie Négrier (14) , Laurence Albiges (6, 15)

1 CRLCC Paul Papin - CRLCC - Centre Paul Papin
2 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
3 Irset - Institut de recherche en santé, environnement et travail
4 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
5 Inflammation, complément et cancer = Inflammation, complement and cancer [CRC]
6 IGR - Institut Gustave Roussy
7 CHU Trousseau [Tours]
8 IPC - Institut Paoli-Calmettes
9 UNICANCER/ICL - Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy]
10 Institut Claudius Regaud
11 CRLCC René Gauducheau
12 Centre Léon Bérard [Lyon]
13 UMR 1015 - Immunologie des tumeurs et immunothérapie
14 UCBL - Université Claude Bernard Lyon 1
15 Département de médecine oncologique [Gustave Roussy]

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.

Domaines: Cancer

Manon de Vries-Brilland, Nathalie Rioux-Leclercq, Maxime Meylan, Jonathan Dauvé, Christophe Passot, et al.. Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma. Journal for Immunotherapy of Cancer, 2023, Journal for ImmunoTherapy of Cancer, 11 (11), pp.e006885. ⟨10.1136/jitc-2023-006885⟩. ⟨hal-04341909⟩